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Sample records for neurofibrillary tangle nft

  1. Neurofibrillary tangles in dementia pugilistica are ubiquitinated.

    OpenAIRE

    Dale, G E; Leigh, P. N.; P. Luthert; Anderton, B H; Roberts, G. W.

    1991-01-01

    Ubiquitin, a protein thought to be involved in the ATP-dependent non-lysosomal degradation of abnormal proteins, has already been identified as a component of neurofibrillary tangles in Alzheimer's disease. We have examined ubiquitin immunoreactivity in a unique collection of brains from 16 ex-boxers including 11 with dementia pugilistica. Neurofibrillary tangles of dementia pugilistica were labelled with an affinity purified antiserum to ubiquitin, and BF10, a monoclonal antibody to a neurof...

  2. Diffuse neurofibrillary tangles with calcification: a new presenile dementia.

    OpenAIRE

    Kosaka, K

    1994-01-01

    The term "diffuse neurofibrillary tangles with calcification" (DNTC) is proposed for a new form of presenile dementia. It is characterised by slowly progressive cortical dementia in the presenium, localised temporal or temporofrontal lobar atrophy, numerous neurofibrillary tangles widespread in the cerebral cortex, and pronounced calcareous deposits; 16 cases of DNTC, have been reported.

  3. Neurofibrillary tangles in some cases of dementia pugilistica share antigens with amyloid beta-protein of Alzheimer's disease.

    OpenAIRE

    Allsop, D; Haga, S; Bruton, C; Ishii, T.; Roberts, G. W.

    1990-01-01

    Formalin-fixed, paraffin-embedded temporal lobe sections from eight former boxers' brains were examined using an immunohistochemical method with antibodies to amyloid beta protein. In accord with recent observations in Alzheimer's disease, significant numbers of beta-protein immunoreactive neurofibrillary tangles (NFT) were observed in three cases. Most of these immunoreactive NFTs appeared to be tombstone tangles, although not all such tangles were stained. This immunoreaction was completely...

  4. Evidence for participation of aluminum in neurofibrillary tangle formation and growth in Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2010-01-01

    This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease.

  5. [F-18]-AV-1451 binding correlates with postmortem neurofibrillary tangle Braak staging.

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    Marquié, Marta; Siao Tick Chong, Michael; Antón-Fernández, Alejandro; Verwer, Eline E; Sáez-Calveras, Nil; Meltzer, Avery C; Ramanan, Prianca; Amaral, Ana C; Gonzalez, Jose; Normandin, Marc D; Frosch, Matthew P; Gómez-Isla, Teresa

    2017-06-13

    [F-18]-AV-1451, a PET tracer specifically developed to detect brain neurofibrillary tau pathology, has the potential to facilitate accurate diagnosis of Alzheimer's disease (AD), staging of brain tau burden and monitoring disease progression. Recent PET studies show that patients with mild cognitive impairment and AD dementia exhibit significantly higher in vivo [F-18]-AV-1451 retention than cognitively normal controls. Importantly, PET patterns of [F-18]-AV-1451 correlate well with disease severity and seem to match the predicted topographic Braak staging of neurofibrillary tangles (NFTs) in AD, although this awaits confirmation. We studied the correlation of autoradiographic binding patterns of [F-18]-AV-1451 and the stereotypical spatiotemporal pattern of progression of NFTs using legacy postmortem brain samples representing different Braak NFT stages (I-VI). We performed [F-18]-AV-1451 phosphor-screen autoradiography and quantitative tau measurements (stereologically based NFT counts and biochemical analysis of tau pathology) in three brain regions (entorhinal cortex, superior temporal sulcus and visual cortex) in a total of 22 cases: low Braak (I-II, n = 6), intermediate Braak (III-IV, n = 7) and high Braak (V-VI, n = 9). Strong and selective [F-18]-AV-1451 binding was detected in all tangle-containing regions matching precisely the observed pattern of PHF-tau immunostaining across the different Braak stages. As expected, no signal was detected in the white matter or other non-tangle containing regions. Quantification of [F-18]-AV-1451 binding was very significantly correlated with the number of NFTs present in each brain region and with the total tau and phospho-tau content as reported by Western blot and ELISA. [F-18]-AV-1451 is a promising biomarker for in vivo quantification of brain tau burden in AD. Neuroimaging-pathologic studies conducted on postmortem material from individuals imaged while alive are now needed to confirm these observations.

  6. Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis.

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    Yamada, Masahito

    2003-12-01

    Senile dementia of the NFT type (SD-NFT) is a subset of dementia in the elderly, characterized by numerous NFT in the hippocampal region and absence or scarcity of senile plaques throughout the brain. Senile dementia-NFT has also been referred to as tangle-only dementia, NFT-predominant form of SD, SD with tangles, or limbic NFT dementia. Herein are proposed the criteria for neuropathological diagnosis of SD-NFT: (i) late-onset dementia with abundant NFT in the hippocampal region and absence or scarcity of senile plaques (amyloid beta protein deposits) throughout the brain; and (ii) exclusion of other dementias with NFT. Some elderly individuals suffering from memory disorder without obvious dementia have neuropathological findings similar to SD-NFT, and they would represent a condition in the process of formation of the SD-NFT pathology. Guidelines for the clinical diagnosis of SD-NFT are also proposed; development of reliable diagnostic tests is necessary to differentiate AD and other neurodegenerative dementias from SD-NFT.

  7. [Primary age-related tauopathy (PART): a novel term to describe age-related tangle pathology encompassing a wide range from cognitively normal condition to senile dementia of the neurofibrillary tangle type].

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    Yamada, Masahito

    2016-03-01

    It has been reported that neurofibrillary tangles (NFTs) are commonly observed in older people, and that some of older individuals with dementia have a large amount of NFTs in the medial temporal lobe without amyloid(Aβ) plaques, which have been referred to as senile dementia of the NFT type (SD-NFT), tangle-predominant senile dementia (TPSD), or tangle-only dementia. In 2014, our international collaborative group proposed a new term, "primary age-related tauopathy(PART)", to describe such age-related tangle pathology, clinically encompassing a wide range from normal to cognitive impairment/ dementia (SD-NFT). This nomenclature would provide a conceptual foundation for future studies leading to development of clinical diagnosis for this condition.

  8. Neuropathologically defined subtypes of Alzheimer's disease differ significantly from neurofibrillary tangle-predominant dementia.

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    Janocko, Nicholas J; Brodersen, Kevin A; Soto-Ortolaza, Alexandra I; Ross, Owen A; Liesinger, Amanda M; Duara, Ranjan; Graff-Radford, Neill R; Dickson, Dennis W; Murray, Melissa E

    2012-11-01

    Alzheimer's disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (n = 18) with LP AD (n = 19), as well as the other AD subtypes, typical AD (n = 52) and HpSp AD (n = 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD. MAPT H1H1 genotype frequency was high (~70 %) in NFTD and LP AD

  9. Factors responsible for neurofibrillary tangles and neuronal cell losses in tauopathy.

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    Wakasaya, Yasuhito; Kawarabayashi, Takeshi; Watanabe, Mitsunori; Yamamoto-Watanabe, Yukiko; Takamura, Ayumi; Kurata, Tomoko; Murakami, Tetsuro; Abe, Koji; Yamada, Kiyofumi; Wakabayashi, Koichi; Sasaki, Atsushi; Westaway, David; Hyslop, Peter St George; Matsubara, Etsuro; Shoji, Mikio

    2011-04-01

    TgTauP301L mice that overexpress the mutant human tauP301L present in FTDP-17 reproduce neurofibrillary tangles (NFTs), neuronal cell losses, memory disturbance, and substantial phenotypic variation. To demonstrate factors responsible for NFT formation and neuronal cell losses, sets of TgTauP301L for comparison with or without NFTs and neuronal cell losses were studied with oligonucleotide microarrays. Gene expressions were altered in biological pathways, including oxidative stress, apoptosis, mitochondrial fatty acid betaoxidation, inflammatory response pathway, and complement and coagulation cascade pathways. Among 24 altered genes, increased levels of apolipoprotein D (ApoD) and neuronal PAS domain protein 4 (Npas4) and decreased levels of doublecortin (DCX) and potassium channel, voltage-gated, shaker-related subfamily, β member 1 (Kcnab1) were found in the TgTauP301L with NFTs and neuronal cell losses, Alzheimer's brains, and tauopathy brains. Thus, many biological pathways and novel molecules are associated with NFT formation and neuronal cell losses in tauopathy brains. Copyright © 2011 Wiley-Liss, Inc.

  10. Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology.

    Science.gov (United States)

    Holler, Christopher J; Davis, Paulina R; Beckett, Tina L; Platt, Thomas L; Webb, Robin L; Head, Elizabeth; Murphy, M Paul

    2014-01-01

    Recent genome wide association studies have implicated bridging integrator 1 (BIN1) as a late-onset Alzheimer's disease (AD) susceptibility gene. There are at least 15 different known isoforms of BIN1, with many being expressed in the brain including the longest isoform (iso1), which is brain-specific and localizes to axon initial segments and nodes of Ranvier. It is currently unknown what role BIN1 plays in AD. We analyzed BIN1 protein expression from a large number (n = 71) of AD cases and controls from five different brain regions (hippocampus, inferior parietal cortex, inferior temporal cortex, frontal cortex (BA9), and superior and middle temporal gyri). We found that the amount of the largest isoform of BIN1 was significantly reduced in the AD brain compared to age-matched controls, and smaller BIN1 isoforms were significantly increased. Further, BIN1 was significantly correlated with the amount of neurofibrillary tangle (NFT) pathology but not with either diffuse or neuritic plaques, or with the amount of amyloid-β peptide. BIN1 is known to be abnormally expressed in another human disease, myotonic dystrophy, which also features prominent NFT pathology. These data suggest that BIN1 is likely involved in AD as a modulator of NFT pathology, and that this role may extend to other human diseases that feature tau pathology.

  11. Quantification of immunohistochemical findings of neurofibrillary tangles and senile plaques for a diagnosis of dementia in forensic autopsy cases.

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    Takayama, Mio; Kashiwagi, Masayuki; Matsusue, Aya; Waters, Brian; Hara, Kenji; Ikematsu, Natsuki; Kubo, Shin-Ichi

    2016-09-01

    We report the quantification of immunohistochemical findings for a diagnosis of dementia in autopsy cases among older decedents. Autopsy cases were selected with the following requirements: >65yo; no head injuries, thermal injuries, or heat stroke; no intracranial lesions; and within 48h of death. Among cases that met all requirements, 10 had a clinical diagnosis of dementia were included in dementia group. Non-dementia group consisted of 38 cases without any record of dementia. To compare these groups, immunohistochemically, beta-amyloid, tau protein, gephyrin, and IL-33 were examined in five regions. Quantitative analysis was performed by collecting with image data analyzed using analysis software. Image data on tau-immunopositive neurofibrillary tangles (NFT) and beta-amyloid-positive senile plaques (SP) were photographed. Criteria for dementia were made by counting and measuring NFT and SP from image data using software. Differences in SP and NFT were effective for discriminating between the two groups. These criteria may reveal the presence and progression of dementia. Total of tau-positive NFT in Ammon's horn (AH) may be useful for diagnosing dementia. When the total is more than 41 in approximately 6mm(2) of AH, the possibility of dementia is considered. Total of beta-amyloid-positive SP in the parahippocampal gyrus (PHG) may be useful for diagnosing dementia. When the total in approximately 5mm(2) of PHG is more than 47, the possibility of dementia is considered. Immunohistochemical staining may be more useful for obtaining image data for quantification than conventional staining techniques, such as Bielschowsky-Hirano's silver staining. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Expression of CD74 is increased in neurofibrillary tangles in Alzheimer's disease

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    Castellani Rudy J

    2008-09-01

    Full Text Available Abstract Alzheimer disease (AD is a chronic neurodegenerative disease that is characterized by progressive memory loss. Pathological markers of AD include neurofibrillary tangles, accumulation of amyloid-β plaques, neuronal loss, and inflammation. The exact events that lead to the neuronal dysfunction and loss are not completely understood. However, pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor α, are increased in AD, along with gene expression of major histocompatibility complex (MHC class II molecules and macrophage migration inhibitory factor (MIF. MHC class II molecules are found in microglia of the brain, while MIF is found in both microglia and neurons of the hypothalamus, hippocampus, and cortex. MIF is not only a lymphocyte mediator but also a pituitary factor with endocrine properties and can mediate phosphorylation of the extracellular signal-regulated kinase-1/2 MAP kinases pathway. In this study, we looked at CD74, an integral membrane protein that acts as both a chaperone for MHC class II molecules as well as a receptor binding site for MIF. CD74 was recently found to be increased in microglia in AD cases compared to age-matched controls, but has not been reported in neurons. In our analysis, immunohistochemistry revealed a significant increase in CD74 primarily in neurofibrillary tangles, amyloid-β plaques, and microglia. This is the first finding to our knowledge that CD74 is increased in neurons of AD cases compared to age-matched control cases.

  13. Methylene blue does not reverse existing neurofibrillary tangle pathology in the rTg4510 mouse model of tauopathy.

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    Spires-Jones, Tara L; Friedman, Taylor; Pitstick, Rose; Polydoro, Manuela; Roe, Allyson; Carlson, George A; Hyman, Bradley T

    2014-03-06

    Alzheimer's disease is characterized pathologically by aggregation of amyloid beta into senile plaques and aggregation of pathologically modified tau into neurofibrillary tangles. While changes in amyloid processing are strongly implicated in disease initiation, the recent failure of amyloid-based therapies has highlighted the importance of tau as a therapeutic target. "Tangle busting" compounds including methylene blue and analogous molecules are currently being evaluated as therapeutics in Alzheimer's disease. Previous studies indicated that methylene blue can reverse tau aggregation in vitro after 10 min, and subsequent studies suggested that high levels of drug reduce tau protein levels (assessed biochemically) in vivo. Here, we tested whether methylene blue could remove established neurofibrillary tangles in the rTg4510 model of tauopathy, which develops robust tangle pathology. We find that 6 weeks of methylene blue dosing in the water from 16 months to 17.5 months of age decreases soluble tau but does not remove sarkosyl insoluble tau, or histologically defined PHF1 or Gallyas positive tangle pathology. These data indicate that methylene blue treatment will likely not rapidly reverse existing tangle pathology. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. An autopsy case of a centenarian with the pathology of senile dementia of the neurofibrillary tangle type.

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    Iwasaki, Yasushi; Deguchi, Akira; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Yoshida, Mari

    2017-03-01

    A Japanese woman showed slowly progressive memory disturbance since the age of 85 years. Later, disorientation gradually appeared. Head computed tomography revealed severe hippocampal atrophy, particularly in the posterior portion, and lateral ventricular dilatation, particularly in the inferior horn at the age of 99 years. The amygdala was relatively preserved from atrophy, and atrophy of the frontal lobe was relatively mild for her age. Apolipoprotein E gene analysis showed the ε3 homozygous phenotype. The woman died at the age of 101 years, and her clinical diagnosis was mild Alzheimer's disease. No apparent behavioural and psychological symptoms of dementia were observed during the disease course. Autopsy revealed severe hippocampal atrophy with numerous neurofibrillary tangles and ghost tangles, particularly in the hippocampal region, but senile plaques were rarely observed in the brain. The pathological findings were compatible with senile dementia of the neurofibrillary tangle type, whereas other neurodegenerative disorders were not recognized. The clinicopathologic findings of the present case are considered significant for the clinical diagnosis and pathogenesis of senile dementia of the neurofibrillary tangle type. © 2016 The Authors. Psychogeriatrics © 2016 Japanese Psychogeriatric Society.

  15. Neurofibrillary tangles and the deposition of a beta amyloid peptide with a novel N-terminal epitope in the brains of wild Tsushima leopard cats.

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    Chambers, James K; Uchida, Kazuyuki; Harada, Tomoyuki; Tsuboi, Masaya; Sato, Masumi; Kubo, Masahito; Kawaguchi, Hiroaki; Miyoshi, Noriaki; Tsujimoto, Hajime; Nakayama, Hiroyuki

    2012-01-01

    Beta amyloid (Aβ) deposits are seen in aged individuals in many of the mammalian species that possess the same Aβ amino acid sequence as humans. Conversely, neurofibrillary tangles (NFT), the other hallmark lesion of Alzheimer's disease (AD), are extremely rare in these animals. We detected Aβ deposits in the brains of Tsushima leopard cats (Prionailurus bengalensis euptilurus) that live exclusively on Tsushima Island, Japan. Aβ42 was deposited in a granular pattern in the neuropil of the pyramidal cell layer, but did not form argyrophilic senile plaques. These Aβ deposits were not immunolabeled with antibodies to the N-terminal of human Aβ. Sequence analysis of the amyloid precursor protein revealed an amino acid substitution at the 7th residue of the Aβ peptide. In a comparison with other mammalian animals that do develop argyrophilic senile plaques, we concluded that the alternative Aβ amino acid sequence displayed by leopard cats is likely to be related to its distinctive deposition pattern. Interestingly, most of the animals with these Aβ deposits also developed NFTs. The distributions of hyperphosphorylated tau-positive cells and the two major isoforms of aggregated tau proteins were quite similar to those seen in Alzheimer's disease. In addition, the unphosphorylated form of GSK-3β colocalized with hyperphosphorylated tau within the affected neurons. In conclusion, this animal species develops AD-type NFTs without argyrophilic senile plaques.

  16. Neurofibrillary tangles and the deposition of a beta amyloid peptide with a novel N-terminal epitope in the brains of wild Tsushima leopard cats.

    Directory of Open Access Journals (Sweden)

    James K Chambers

    Full Text Available Beta amyloid (Aβ deposits are seen in aged individuals in many of the mammalian species that possess the same Aβ amino acid sequence as humans. Conversely, neurofibrillary tangles (NFT, the other hallmark lesion of Alzheimer's disease (AD, are extremely rare in these animals. We detected Aβ deposits in the brains of Tsushima leopard cats (Prionailurus bengalensis euptilurus that live exclusively on Tsushima Island, Japan. Aβ42 was deposited in a granular pattern in the neuropil of the pyramidal cell layer, but did not form argyrophilic senile plaques. These Aβ deposits were not immunolabeled with antibodies to the N-terminal of human Aβ. Sequence analysis of the amyloid precursor protein revealed an amino acid substitution at the 7th residue of the Aβ peptide. In a comparison with other mammalian animals that do develop argyrophilic senile plaques, we concluded that the alternative Aβ amino acid sequence displayed by leopard cats is likely to be related to its distinctive deposition pattern. Interestingly, most of the animals with these Aβ deposits also developed NFTs. The distributions of hyperphosphorylated tau-positive cells and the two major isoforms of aggregated tau proteins were quite similar to those seen in Alzheimer's disease. In addition, the unphosphorylated form of GSK-3β colocalized with hyperphosphorylated tau within the affected neurons. In conclusion, this animal species develops AD-type NFTs without argyrophilic senile plaques.

  17. Linking traumatic brain injury to chronic traumatic encephalopathy: identification of potential mechanisms leading to neurofibrillary tangle development.

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    Lucke-Wold, Brandon Peter; Turner, Ryan Coddington; Logsdon, Aric Flint; Bailes, Julian Edwin; Huber, Jason Delwyn; Rosen, Charles Lee

    2014-07-01

    Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

  18. Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study

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    Liu, Joan Y.W.; Thompson, Pam; Phadke, Rahul; Narkiewicz, Marta; Martinian, Lillian; Marsdon, Derek; Koepp, Matthias; Caboclo, Luis; Catarino, Claudia B.; Sisodiya, Sanjay M.

    2011-01-01

    The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P epilepsy series (P type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy. PMID:21903728

  19. Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study.

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    Thom, Maria; Liu, Joan Y W; Thompson, Pam; Phadke, Rahul; Narkiewicz, Marta; Martinian, Lillian; Marsdon, Derek; Koepp, Matthias; Caboclo, Luis; Catarino, Claudia B; Sisodiya, Sanjay M

    2011-10-01

    The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P brain injury (P pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

  20. AAV-tau mediates pyramidal neurodegeneration by cell-cycle re-entry without neurofibrillary tangle formation in wild-type mice.

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    Tomasz Jaworski

    Full Text Available In Alzheimer's disease tauopathy is considered secondary to amyloid, and the duality obscures their relation and the definition of their respective contributions.Transgenic mouse models do not resolve this problem conclusively, i.e. the relative hierarchy of amyloid and tau pathology depends on the actual model and the genes expressed or inactivated. Here, we approached the problem in non-transgenic models by intracerebral injection of adeno-associated viral vectors to express protein tau or amyloid precursor protein in the hippocampus in vivo. AAV-APP mutant caused neuronal accumulation of amyloid peptides, and eventually amyloid plaques at 6 months post-injection, but with only marginal hippocampal cell-death. In contrast, AAV-Tau, either wild-type or mutant P301L, provoked dramatic degeneration of pyramidal neurons in CA1/2 and cortex within weeks. Tau-mediated neurodegeneration proceeded without formation of large fibrillar tau-aggregates or tangles, but with increased expression of cell-cycle markers.We present novel AAV-based models, which demonstrate that protein tau mediates pyramidal neurodegeneration in vivo. The data firmly support the unifying hypothesis that post-mitotic neurons are forced to re-enter the cell-cycle in primary and secondary tauopathies, including Alzheimer's disease.

  1. Antibodies to presenilin proteins detect neurofibrillary tangles in Alzheimer's disease

    National Research Council Canada - National Science Library

    Murphy, GM, Jr; Forno, LS; Ellis, WG; Nochlin, D; Levy-Lahad, E; Poorkaj, P; Bird, TD; Jiang, Z; Cordell, B

    1996-01-01

    GM Murphy Jr, LS Forno, WG Ellis, D Nochlin, E Levy-Lahad, P Poorkaj, TD Bird, Z Jiang and B Cordell Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, California, USA...

  2. Hippocampal connectivity and Alzheimer's dementia: effects of synapse loss and tangle frequency in a two-component model.

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    Samuel, W; Masliah, E; Hill, L R; Butters, N; Terry, R

    1994-11-01

    Our prior research on patients with Alzheimer's disease (AD) found a high correspondence between premortem dementia and accumulation of neurofibrillary tangles (NFTs) with concurrent loss of synapse density in several brain regions. In the present study, we examined these same clinicopathologic relationships in the context of seven subregions of the hippocampal formation using a sample of 16 AD patients who had been administered three well-known mental status tests antemortem. We found NFT counts to be most strongly correlated with degree of dementia when they were seen in CA1, the subiculum, and CA4; NFTs in these subregions appeared significantly clustered on factor analysis. Synapse loss was most strongly correlated with dementia when it occurred in the molecular layers of the dentate fasciculus and stratum lacunosum, CA2/3, and CA4; synapse loss in these subregions appeared significantly clustered on factor analysis. In general, these results were compatible with a two-component model of hippocampal connectivity and function in the context of AD. The first component consists of subregions preceding CA1 in a hypothesized input-processing sequence intrinsic to the hippocampus that summates neuronal excitation and that influences cognition primarily through synapse density. The second component consists of an "output module," mainly CA1 and the subiculum, that receives the processed signal, passes it on to extrahippocampal cortical and subcortical targets, and affects cognition primarily by NFT accumulation in output neurons. A "net pathology" score combining standardized z-scores for synapse density and NFTs was significantly correlated with all three mental status measures in all hippocampal subregions except the entorhinal cortex, and stepwise regressions on these data found net pathology in CA4 to be the most independent significant predictor of premortem dementia.

  3. Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain.

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    Day, Ryan J; Mason, Maria J; Thomas, Chloe; Poon, Wayne W; Rohn, Troy T

    2015-01-01

    Vascular dementia (VaD) is the second most common form of dementia in the United States and is characterized as a cerebral vessel vascular disease that leads to ischemic episodes. Whereas the relationship between caspase-cleaved tau and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) has been previously described, whether caspase activation and cleavage of tau occurs in VaD is presently unknown. To investigate a potential role for caspase-cleaved tau in VaD, we analyzed seven confirmed cases of VaD by immunohistochemistry utilizing a well-characterized antibody that specifically detects caspase-cleaved tau truncated at Asp421. Application of this antibody (TauC3) revealed consistent labeling within NFTs, dystrophic neurites within plaque-rich regions and corpora amylacea (CA) in the human VaD brain. Labeling of CA by the TauC3 antibody was widespread throughout the hippocampus proper, was significantly higher compared to age matched controls, and co-localized with ubiquitin. Staining of the TauC3 antibody co-localized with MC-1, AT8, and PHF-1 within NFTs. Quantitative analysis indicated that roughly 90% of PHF-1-labeled NFTs contained caspase-cleaved tau. In addition, we documented the presence of active caspase-3 within plaques, blood vessels and pretangle neurons that co-localized with TauC3. Collectively, these data support a role for the activation of caspase-3 and proteolytic cleavage of TauC3 in VaD providing further support for the involvement of this family of proteases in NFT pathology.

  4. Nutrient Film Technique (NFT Hydroponic Monitoring System

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    Helmy Helmy

    2016-10-01

    Full Text Available Plant cultivation using hydroponic is very popular today. Nutrient Film Technique (NFT hydroponic system is commonly used by people. It can be applied indoor or outdoor. Plants in this systemneed nutrient solution to grow well. pH, TDS and temperature of the nutrient solution must be check to ensure plant gets sufficient nutrients. This research aims todevelop monitoring system of NFT hydroponic. Farmer will be able to monitor pH, TDS and temperature online. It will ease farmer to decide which plant is suitable to be cultivated and time to boost growth.Delay of the system will be measured to know system performance. Result shows that pH is directly proportional with TDS. Temperature value has no correlation with pH and TDS. System has highest delay during daylight and afternoon but it will decline in the night and morning. Average of delay in the morning is 11 s, 28.5 s in daylight, 32 s in the afternoon and 17.5 s in the night.

  5. Computing with Colored Tangles

    Directory of Open Access Journals (Sweden)

    Avishy Y. Carmi

    2015-07-01

    Full Text Available We suggest a diagrammatic model of computation based on an axiom of distributivity. A diagram of a decorated colored tangle, similar to those that appear in low dimensional topology, plays the role of a circuit diagram. Equivalent diagrams represent bisimilar computations. We prove that our model of computation is Turing complete and with bounded resources that it can decide any language in complexity class IP, sometimes with better performance parameters than corresponding classical protocols.

  6. Diffuse neurofibrillary tangles with calcification (Kosaka–Shibayama disease) in Japan

    National Research Council Canada - National Science Library

    Ukai, Katsuyuki; Kosaka, Kenji

    2016-01-01

    ... ’ was initially proposed by Kosaka in 1994. Although 26 autopsies and 21 clinical patients with DNTC have been described in Japan to date, DNTC has rarely been reported in the European and North American published work...

  7. Greenhouse spinach production in a NFT system.

    Science.gov (United States)

    Both, A J; Leed, A R; Goto, E; Albright, L D; Langhans, R W

    1996-12-01

    Primed spinach (Spinacia oleracea L., cv. Nordic) seed was started in rockwool slabs in a growth room for eight days before the seedlings were transplanted into a controlled environment greenhouse equipped with five identical, but separate, NFT systems. The day and night temperatures in the greenhouse were maintained at 24 and 18 degrees C, respectively, with the daytime starting at 06:00 and ending at 22:00 hr. A photoperiod of 16 hrs was maintained, to prevent early bolting, and different target daily integrated light levels (PPF, in mol m-2 d-1) were studied to observe dry weight production. HPS lamps were used as the supplemental light source. Thirty-three days after seeding a final harvest was performed. Using the expolinear growth equation, dry weight production can be predicted based solely on target daily integrated light levels. Total chlorine residuals in the nutrient solution higher than 1 ppm were observed to be toxic. Root disease (rot) in the plant crown was found to be caused by Fusarium. Several remedies, including three biofungicides and potassium silicate, were tried but none proved to be consistently successful.

  8. Interaction of Aluminum with PHFτ in Alzheimer’s Disease Neurofibrillary Degeneration Evidenced by Desferrioxamine-Assisted Chelating Autoclave Method

    Science.gov (United States)

    Murayama, Harunobu; Shin, Ryong-Woon; Higuchi, Jun; Shibuya, Satoshi; Muramoto, Tamaki; Kitamoto, Tetsuyuki

    1999-01-01

    To demonstrate that aluminum III (Al) interacts with PHFτ in neurofibrillary degeneration (NFD) of Alzheimer’s disease (AD) brain, we developed a “chelating autoclave method” that allows Al chelation by using trivalent-cationic chelator desferrioxamine. Its application to AD brain sections before Morin histochemistry for Al attenuated the positive fluorescence of neurofibrillary tangles, indicating Al removal from them. This method, applied for immunostaining with phosphorylation-dependent anti-τ antibodies, significantly enhanced the PHFτ immunoreactivity of the NFD. These results suggest that each of the phosphorylated epitopes in PHFτ are partially masked by Al binding. Incubation of AD sections with AlCl3 before Morin staining revealed Al accumulation with association to neurofibrillary tangles. Such incubation before immunostaining with the phosphorylation-dependent anti-τ antibodies abolished the immunolabeling of the NFD and this abolition was reversed by the Al chelation. These findings indicate cumulative Al binding to and thereby antigenic masking of the phosphorylated epitopes of PHFτ. Al binding was further documented for electrophoretically-resolved PHFτ on immunoblots, indicating direct Al binding to PHFτ. In vitro aggregation by AlCl3 was observed for PHFτ but was lost on dephosphorylation of PHFτ. Taken together, phosphorylation-dependent and direct PHFτ-Al interaction occurs in the NFD of the AD brain. PMID:10487845

  9. Human Truncated Tau Induces Mature Neurofibrillary Pathology in a Mouse Model of Human Tauopathy.

    Science.gov (United States)

    Zimova, Ivana; Brezovakova, Veronika; Hromadka, Tomas; Weisova, Petronela; Cubinkova, Veronika; Valachova, Bernadeta; Filipcik, Peter; Jadhav, Santosh; Smolek, Tomas; Novak, Michal; Zilka, Norbert

    2016-09-06

    Alzheimer's disease (AD) represents the most common neurodegenerative disorder. Several animal models have been developed in order to test pathophysiological mechanisms of the disease and to predict effects of pharmacological interventions. Here we examine the molecular and behavioral features of R3m/4 transgenic mice expressing human non-mutated truncated tau protein (3R tau, aa151-391) that were previously used for efficacy testing of passive tau vaccine. The mouse model reliably recapitulated crucial histopathological features of human AD, such as pre-tangles, neurofibrillary tangles, and neuropil threads. The pathology was predominantly located in the brain stem. Transgenic mice developed mature sarkosyl insoluble tau complexes consisting of mouse endogenous and human truncated and hyperphosphorylated forms of tau protein. The histopathological and biochemical features were accompanied by significant sensorimotor impairment and reduced lifespan. The sensorimotor impairment was monitored by a highly sensitive, fully-automated tool that allowed us to assess early deficit in gait and locomotion. We suggest that the novel transgenic mouse model can serve as a valuable tool for analysis of the therapeutic efficacy of tau vaccines for AD therapy.

  10. [{sup 18}F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Harada, Ryuichi [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Okamura, Nobuyuki [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Furumoto, Shozo [Tohoku University, Frontier Research Institute for Interdisciplinary Science, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Furukawa, Katsutoshi; Ishiki, Aiko; Tomita, Naoki; Arai, Hiroyuki [Tohoku University, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Sendai (Japan); Hiraoka, Kotaro; Watanuki, Shoichi; Miyake, Masayasu; Matsuda, Rin; Inami, Akie; Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Shidahara, Miho [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tohoku University School of Medicine, Division of Medical Physics, Sendai (Japan); Ishikawa, Yoichi; Tago, Tetsuro; Funaki, Yoshihito; Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Yoshikawa, Takeo; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Division of Neuro-imaging, Institute of Development, Aging and Cancer, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan)

    2015-03-20

    Visualization of the spatial distribution of neurofibrillary tangles would help in the diagnosis, prevention and treatment of dementia. The purpose of the study was to evaluate the clinical utility of [{sup 18}F]THK-5117 as a highly selective tau imaging radiotracer. We initially evaluated in vitro binding of [{sup 3}H]THK-5117 in post-mortem brain tissues from patients with Alzheimer's disease (AD). In clinical PET studies, [{sup 18}F]THK-5117 retention in eight patients with AD was compared with that in six healthy elderly controls. Ten subjects underwent an additional [{sup 11}C]PiB PET scan within 2 weeks. In post-mortem brain samples, THK-5117 bound selectively to neurofibrillary deposits, which differed from the binding target of PiB. In clinical PET studies, [{sup 18}F]THK-5117 binding in the temporal lobe clearly distinguished patients with AD from healthy elderly subjects. Compared with [{sup 11}C]PiB, [{sup 18}F]THK-5117 retention was higher in the medial temporal cortex. These findings suggest that [{sup 18}F]THK-5117 provides regional information on neurofibrillary pathology in living subjects. (orig.)

  11. Alzheimer's disease neurofibrillary degeneration: pivotal and multifactorial.

    Science.gov (United States)

    Iqbal, Khalid; Wang, Xiaochuan; Blanchard, Julie; Liu, Fei; Gong, Cheng-Xin; Grundke-Iqbal, Inge

    2010-08-01

    Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Abeta(1-42) (where Abeta is amyloid beta-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I(2)(PP2A)) of PP2A (protein phosphatase 2A) at Asn(175) into N-terminal (I(2NTF)) and C-terminal (I(2CTF)) halves and their translocation from the neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I(2CTF) in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage of I(2)(PP2A)/SET offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.

  12. Production of calla lily grown in an NFT system

    Directory of Open Access Journals (Sweden)

    Paulo Roberto Correa Landgraf

    2017-12-01

    Full Text Available The objective of this study was to evaluate the production of calla lily in an NFT system. The experiment was carried out in a greenhouse, using a 2 x 2 factorial scheme in a completely randomized design (CRD, with fifteen replications. The treatments were a combination of two hydroponic profiles (100 and 150 mm of height and two nutrient solutions. Calla lily plantlets obtained from rhizome buds in trays containing nutrient solution, were transferred to a laminar flow of nutrients, and the experiment lasted 12 months. The height of stems and inflorescences were evaluated, as well as the length and diameter of the inflorescence, the number of flowers per plant and number of flowers per m2 . Growing calla lily plants in an NFT system is feasible. The nutrient solution with the highest concentration of nutrients, particularly N and K, and the profile of 150 mm, are the most suitable for the production of calla lily as a cut flower in a laminar flow of nutrients.

  13. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy

    National Research Council Canada - National Science Library

    Iba, Michiyo; Guo, Jing L; McBride, Jennifer D; Zhang, Bin; Trojanowski, John Q; Lee, Virginia M-Y

    2013-01-01

    ...) comprising filamentous tau protein. Although emerging evidence suggests that tau pathology may be transmitted, we demonstrate here that synthetic tau fibrils are sufficient to transmit tau inclusions in a mouse model...

  14. Implementasi Fuzzy Logic Controller Untuk Mengatur Ph Nutrisi Pada Sistem Hidroponik Nutrient Film Technique (NFT)

    OpenAIRE

    Pancawati, Dian; Yulianto, Andik

    2016-01-01

    One solution to solve limited agricultural land is applying hydroponics Nutrient Film Technique (NFT). The advantage of NFT is using water circulated as a growing medium in order to obtain water, nutrients and oxygen to accelerate the growth of plants with good results. The most important parameter is the pH of nutrients. This article discusses how to design an automatic nutritional pH control system by implementing the method of Fuzzy Logic Controller. The control system use Arduino Mega2560...

  15. Implementasi Fuzzy Logic Controller untuk Mengatur Ph Nutrisi pada Sistem Hidroponik Nutrient Film Technique (NFT)

    OpenAIRE

    Dian Pancawati; Andik Yulianto

    2016-01-01

    One solution to solve limited agricultural land is applying hydroponics Nutrient Film Technique (NFT). The advantage of NFT is using water circulated as a growing medium in order to obtain water, nutrients and oxygen to accelerate the growth of plants with good results. The most important parameter is the pH of nutrients. This article discusses how to design an automatic nutritional pH control system by implementing the method of Fuzzy Logic Controller. The control system use Arduino Mega2560...

  16. Seidel-Smith cohomology for tangles

    DEFF Research Database (Denmark)

    Rezazadegan, Reza

    2009-01-01

    We generalize the “symplectic Khovanov cohomology” of Seidel and Smith (Duke Math J 134(3):453–514, 2006) to tangles using the notion of symplectic valued topological field theory introduced by Wehrheim and Woodward (arXiv:0905.1368).......We generalize the “symplectic Khovanov cohomology” of Seidel and Smith (Duke Math J 134(3):453–514, 2006) to tangles using the notion of symplectic valued topological field theory introduced by Wehrheim and Woodward (arXiv:0905.1368)....

  17. Mutual information in the Tangled Nature Model

    DEFF Research Database (Denmark)

    Jones, Dominic; Sibani, Paolo

    2010-01-01

    We consider the concept of mutual information in ecological networks, and use this idea to analyse the Tangled Nature model of co-evolution. We show that this measure of correlation has two distinct behaviours depending on how we define the network in question: if we consider only the network...

  18. Tau accumulation in the nucleus accumbens in tangle-predominant dementia

    Science.gov (United States)

    2014-01-01

    Background Tangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD. Results We investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms. Conclusions To our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural

  19. Plaques and tangles as well as Lewy-type alpha synucleinopathy are associated with formed visual hallucinations.

    Science.gov (United States)

    Jacobson, Sandra A; Morshed, Trisha; Dugger, Brittany N; Beach, Thomas G; Hentz, Joseph G; Adler, Charles H; Shill, Holly A; Sabbagh, Marwan N; Belden, Christine M; Sue, Lucia I; Caviness, John N; Hu, Chengcheng

    2014-09-01

    Previous research has linked complex or formed visual hallucinations (VH) to Lewy-type alpha-synucleinopathy (LTS) in neocortical and limbic areas. As Alzheimer's disease pathology often co-occurs with LTS, we questioned whether this pathology - amyloid plaques and neurofibrillary tangles - might also be linked to VH. We performed a semi-quantitative neuropathological study across brainstem, limbic, and cortical structures in subjects with a documented clinical history of VH and a clinicopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), or dementia with Lewy bodies (DLB). 173 subjects - including 50 with VH and 123 without VH - were selected from the Arizona Study of Aging and Neurodegenerative Disorders. Clinical variables examined included the Mini-mental State Exam, Hoehn & Yahr stage, and total dopaminergic medication dose. Neuropathological variables examined included total and regional LTS and plaque and tangle densities. A significant relationship was found between the density of LTS and the presence of VH in PD, AD, and DLB. Plaque and tangle densities also were associated with VH in PD (p = .003 for plaque and p = .004 for tangles) but not in AD, where densities were high regardless of the presence of hallucinations. Furthermore, with DLB cases excluded, comorbidity of PD and AD was significantly more prevalent among subjects + VH than subjects -VH (p < .001). These findings suggest that both AD and PD neuropathology contribute to the pathogenesis of VH. Incident VH could be predictive of concomitant AD/PD pathology even when criteria are not met for a second diagnosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) phosphorylate tau protein and are activated in tangle-bearing neurons in Alzheimer disease.

    Science.gov (United States)

    Tavares, Ignatius A; Touma, Dona; Lynham, Steven; Troakes, Claire; Schober, Megan; Causevic, Mirsada; Garg, Ritu; Noble, Wendy; Killick, Richard; Bodi, Istvan; Hanger, Diane P; Morris, Jonathan D H

    2013-05-24

    In Alzheimer disease (AD), the microtubule-associated protein tau is highly phosphorylated and aggregates into characteristic neurofibrillary tangles. Prostate-derived sterile 20-like kinases (PSKs/TAOKs) 1 and 2, members of the sterile 20 family of kinases, have been shown to regulate microtubule stability and organization. Here we show that tau is a good substrate for PSK1 and PSK2 phosphorylation with mass spectrometric analysis of phosphorylated tau revealing more than 40 tau residues as targets of these kinases. Notably, phosphorylated residues include motifs located within the microtubule-binding repeat domain on tau (Ser-262, Ser-324, and Ser-356), sites that are known to regulate tau-microtubule interactions. PSK catalytic activity is enhanced in the entorhinal cortex and hippocampus, areas of the brain that are most susceptible to Alzheimer pathology, in comparison with the cerebellum, which is relatively spared. Activated PSK is associated with neurofibrillary tangles, dystrophic neurites surrounding neuritic plaques, neuropil threads, and granulovacuolar degeneration bodies in AD brain. By contrast, activated PSKs and phosphorylated tau are rarely detectible in immunostained control human brain. Our results demonstrate that tau is a substrate for PSK and suggest that this family of kinases could contribute to the development of AD pathology and dementia.

  1. Real-time fMRI data for testing OpenNFT functionality.

    Science.gov (United States)

    Koush, Yury; Ashburner, John; Prilepin, Evgeny; Sladky, Ronald; Zeidman, Peter; Bibikov, Sergei; Scharnowski, Frank; Nikonorov, Artem; Van De Ville, Dimitri

    2017-10-01

    Here, we briefly describe the real-time fMRI data that is provided for testing the functionality of the open-source Python/Matlab framework for neurofeedback, termed Open NeuroFeedback Training (OpenNFT, Koush et al. [1]). The data set contains real-time fMRI runs from three anonymized participants (i.e., one neurofeedback run per participant), their structural scans and pre-selected ROIs/masks/weights. The data allows for simulating the neurofeedback experiment without an MR scanner, exploring the software functionality, and measuring data processing times on the local hardware. In accordance with the descriptions in our main article, we provide data of (1) periodically displayed (intermittent) activation-based feedback; (2) intermittent effective connectivity feedback, based on dynamic causal modeling (DCM) estimations; and (3) continuous classification-based feedback based on support-vector-machine (SVM) estimations. The data is available on our public GitHub repository: https://github.com/OpenNFT/OpenNFT_Demo/releases.

  2. Lipids: Part of the tangled web

    Energy Technology Data Exchange (ETDEWEB)

    Krauss, R.M.

    1992-08-01

    Analysis of LDL subclasses by non-denaturing gradient gel electrophoresis has led to the identification of a subclass pattern characterized by predominance of small LDL, designated LDL subclass pattern B. The prevalence of pattern B in the general population is approximately 25%, but varies as a function of age and gender, being relatively uncommon in children and in premenopausal women. The remainder of the population has a predominance of larger LDL (pattern A) or an intermediate pattern. Our findings indicate that LDL subclass pattern B is an integral part of the tangled web'' of interrelated coronary disease risk factors associated with insulin resistance. It may be that the pathologic features of this lipoprotein profile, including the relative atherogenicity of small, dense LDL and IDL, contribute importantly to the increased risk of cardiovascular disease in subjects with insulin resistance and hypertension. Furthermore, pattern B serves as a marker for a common genetic trait which may underlie a substantial portion of the familial predisposition to coronary artery disease in the general population. Studies of hormonal, dietary, and pharmacologic influences on expression of this atherogenic phenotype should lead to more effective identification and management of high-risk individuals, and improved approaches to disease prevention in high-risk families.

  3. Lipids: Part of the tangled web

    Energy Technology Data Exchange (ETDEWEB)

    Krauss, R.M.

    1992-08-01

    Analysis of LDL subclasses by non-denaturing gradient gel electrophoresis has led to the identification of a subclass pattern characterized by predominance of small LDL, designated LDL subclass pattern B. The prevalence of pattern B in the general population is approximately 25%, but varies as a function of age and gender, being relatively uncommon in children and in premenopausal women. The remainder of the population has a predominance of larger LDL (pattern A) or an intermediate pattern. Our findings indicate that LDL subclass pattern B is an integral part of the ``tangled web`` of interrelated coronary disease risk factors associated with insulin resistance. It may be that the pathologic features of this lipoprotein profile, including the relative atherogenicity of small, dense LDL and IDL, contribute importantly to the increased risk of cardiovascular disease in subjects with insulin resistance and hypertension. Furthermore, pattern B serves as a marker for a common genetic trait which may underlie a substantial portion of the familial predisposition to coronary artery disease in the general population. Studies of hormonal, dietary, and pharmacologic influences on expression of this atherogenic phenotype should lead to more effective identification and management of high-risk individuals, and improved approaches to disease prevention in high-risk families.

  4. Oh What a Tangled Biofilm Web Bacteria Weave

    Science.gov (United States)

    ... Home Page Oh What a Tangled Biofilm Web Bacteria Weave By Elia Ben-Ari Posted May 1, ... a suitable surface, some water and nutrients, and bacteria will likely put down stakes and form biofilms. ...

  5. Implementasi Fuzzy Logic Controller untuk Mengatur Ph Nutrisi pada Sistem Hidroponik Nutrient Film Technique (NFT

    Directory of Open Access Journals (Sweden)

    Dian Pancawati

    2016-07-01

    Full Text Available One solution to solve limited agricultural land is applying hydroponics Nutrient Film Technique (NFT. The advantage of NFT is using water circulated as a growing medium in order to obtain water, nutrients and oxygen to accelerate the growth of plants with good results. The most important parameter is the pH of nutrients. This article discusses how to design an automatic nutritional pH control system by implementing the method of Fuzzy Logic Controller. The control system use Arduino Mega2560, Analog pH Meter Kit as input, and the solenoid valve as actuators. The best response of the implementation of Fuzzy Logic Controller with the system which has 25 rules. The response shows that the system has in 1200 millisecond rise time and the steady state in 5530 milliseconds to increase the pH. While to decrease the pH system has response of rise time at 2000 milliseconds and steady state at the time of 3000 milliseconds. The system is able to maintain the pH at 5.5, with the result of the growth of lettuce as high as 20 cm and seven leaves for 54 days.

  6. The Solubilization of Model Alzheimer Tangles: Reversing the β-Sheet Conformation Induced by Aluminum with Silicates

    Science.gov (United States)

    Fasman, Gerald D.; Moore, Cathy D.

    1994-11-01

    Neurofibrillary tangles are one of two lesions found in the brain of Alzheimer disease victims. With synthetic peptide fragments of human neurofilament NF-M17 (Glu-Glu-Lys-Gly-Lys-Ser-Pro-Val-Pro-Lys-Ser-Pro-Val-Glu-Glu-Lys-Gly, phosphorylated and unphosphorylated), CD studies were done to examine the effect of sodium orthosilicate on the conformational state produced by Al3+ on fragments of neuronal proteins. Previous studies had shown a conformational transition from α-helix and random to β-pleated sheet upon addition of Al3+ to both phosphorylated and unphosphorylated peptides. If sufficient quantities of Al3+ are added, the peptide precipitates from solution. The ability to reverse or slow the progression of aggregation was examined. Al3+ binding was reversed with 1-2 molar equivalents of sodium orthosilicate (with respect to Al3+), altering the conformation from β-sheet to random coil and resulting in a CD spectrum similar to that of the initial peptide. The tight binding of the SiO4-_4 with the Al3+ provides the mechanism for this transition. These results provide additional information toward understanding the role of aluminum in the Alzheimer diseased brain and suggest the investigation of the possible use of silicates as a therapeutic agent.

  7. PENERAPAN PANJANG TALANG DAN JARAK TANAM DENGAN SISTEM HIDROPONIK NFT (Nutrient Film Technique PADA TANAMAN KAILAN (Brassica oleraceae var. alboglabra

    Directory of Open Access Journals (Sweden)

    Daviv Zali Vidianto

    2013-09-01

    Full Text Available Kailan vegetables is one kind of high economic value that can be grown in hydroponic NFT (Nutrient Film Technique. The purpose of this study to determine the effect of chamfer length and spacing of the system hydroponic NFT (Nutrient Film Technique on the growth and yield kailan (Brassica oleraceae var. Alboglabra. The research has been done in the greenhouse of the Faculty of Agriculture, University Department Agroekoteknologi Trunojoyo Madura District Kamal village Telang Bangkalan. Tat is was conducted in February-May 2012. Research using methods completely randomized design (CRD with non factorial treatment chamfer length 2 m with spacing of 15 cm (P1J1, chamfer length 2 m with spacing of 20 cm (P1J2, chamfer length of 4 m with spacing of 15 cm (P2J1 and chamfer length of 4 m with spacing of 20 cm (P2J2. The materials used are kailan seeds, fertilizers and hydroponics Goodplant acetic acid (CH3COOH. Observations were analyzed using analysis of variance and Duncan continued Test Distance (UJD level of 5%. P1J1 (chamfer length of 2 meters and 15 cm plant spacing gives the best effect on the variable root length, number of leaves and plant canopy wet weight. The treatment does’n effect to variable leaf area, root wet weight, dry weight, and root dry weight of the plant canopyKeyword : Brassica oleraceae var. Alboglabra, hydroponik NFT, chamfer length and spacing

  8. Tangle-Free Finite Element Mesh Motion for Ablation Problems

    Science.gov (United States)

    Droba, Justin

    2016-01-01

    Mesh motion is the process by which a computational domain is updated in time to reflect physical changes in the material the domain represents. Such a technique is needed in the study of the thermal response of ablative materials, which erode when strong heating is applied to the boundary. Traditionally, the thermal solver is coupled with a linear elastic or biharmonic system whose sole purpose is to update mesh node locations in response to altering boundary heating. Simple mesh motion algorithms rely on boundary surface normals. In such schemes, evolution in time will eventually cause the mesh to intersect and "tangle" with itself, causing failure. Furthermore, such schemes are greatly limited in the problems geometries on which they will be successful. This paper presents a comprehensive and sophisticated scheme that tailors the directions of motion based on context. By choosing directions for each node smartly, the inevitable tangle can be completely avoided and mesh motion on complex geometries can be modeled accurately.

  9. The Tangled Nature Model of evolutionary dynamics reconsidered

    DEFF Research Database (Denmark)

    Andersen, Christian Walther; Sibani, Paolo

    2016-01-01

    The Tangled Nature Model of biological and cultural evolution features interacting agents which compete for limited resources and reproduce in an error prone fashion and at a rate depending on the `tangle' of interactions they maintain with others. The set of interactions linking a TNM individual...... all the interactions, while increasing $K$ up to the length of the genome ensures an increasing level of trait inheritance. We show that the distribution of the interactions generated by our rule is nearly independent of the value of $K$. Changing $K$ strengthens the core structure of the ecology......, leads to population abundance distributions which are better approximated by log-normal probability densities and increases the probability that a species extant at time $t_{\\rm w}$ is also extant at a later time $t$. In particular, survival probabilities are shown to decay as powers of the ratio $t...

  10. Expression of Alzheimer-Type Neurofibrillary Epitopes in Primary Rat Cortical Neurons Following Infection with Enterococcus faecalis.

    Science.gov (United States)

    Underly, Robert; Song, Mee-Sook; Dunbar, Gary L; Weaver, Charles L

    2015-01-01

    The neurofibrillary tau pathology and amyloid deposits seen in Alzheimer's disease (AD) also have been seen in bacteria-infected brains. However, few studies have examined the role of these bacteria in the generation of tau pathology. One suggested link between infection and AD is edentulism, the complete loss of teeth. Edentulism can result from chronic periodontal disease due to infection by Enterococcus faecalis. The current study assessed the ability to generate early Alzheimer-like neurofibrillary epitopes in primary rat cortical neurons through bacterial infection by E. faecalis. Seven-day old cultured neurons were infected with E. faecalis for 24 and 48 h. An upward molecular weight shift in tau by Western blotting (WB) and increased appearance of tau reactivity in cell bodies and degenerating neurites was found in the 48 h infection group for the antibody CP13 (phospho-Serine 202). A substantial increase in reactivity of Alz-50 was seen at 24 and 48 h after infection. Furthermore, extensive microtubule-associated protein 2 (MAP2) reactivity also was seen at 24 and 48 h post-infection. Our preliminary findings suggest a potential link between E. faecalis infection and intracellular changes that may help facilitate early AD-like neurofibrillary pathology. HighlightsEnterococcus faecalis used in the generation of AD neurofibrillary epitopes in rat.Infection increases Alz-50, phospho-Serine 202 tau, and MAP2 expression.Infection by Enterococcus may play a role in early Alzheimer neurofibrillary changes.

  11. Efluente y té de vermicopost en la producción de hortalizas de hoja en sistema NFT.

    OpenAIRE

    González Solano, Karla Daniela

    2013-01-01

    El objetivo de la presente investigación fue determinar la calidad nutrimental del efluente y té de vermicompost en la producción de hortalizas de hoja producidas bajo un sistema NFT (Nutrient Film Technique). Para cumplir el objetivo se llevaron a cabo cinco investigaciones donde se incluye desde identificar el origen del vermicompost, las características químicas ideales para obtener un té de vermicompost hasta su evaluación nutrimental en hortalizas y aromáticas. Los resultados obtenidos ...

  12. Efluente y té de vermicompost en la producción de hortalizas de hoja en sistema NFT

    OpenAIRE

    Karla D. González Solano

    2013-01-01

    Se comparó los efectos de té y efluente de vermicompost con la solución nutritiva Steiner en tres especies vegetales en un siste-ma hidropónico NFT (Nutrient Film Technique). El experimento se reliazó en Montecillo, Texcoco, Estado de México, en inverna-dero tipo túnel, de mayo a agosto 2012. Las especies y cultivares utilizados fueron: albahaca (Ocimum basilicum L.) cv Minimum, cilantro (Coriandrum sativum L.) cv Caribe, y lechuga (Lactu-ca sativa L.) cv Escala. La solución nutritiva mineral...

  13. Experiencia de producción de lechuga americana (Lactuca sativa hidropónica, tipo NFT

    Directory of Open Access Journals (Sweden)

    Laura Brenes-Peralta

    2014-06-01

    En el Centro de Prácticas Docentes e Investigación Agropecuaria de la Escuela de Agronegocios del Instituto Tecnológico de Costa Rica (TEC se cuenta, actualmente, con un sistema de este tipo NFT donde estableció una actividad de fortalecimiento que ha resultado en la observación de ciertas características a partir de la experiencia generada, de la cual se espera fomentar el uso de la hidroponía, así como divulgar información técnica y de buenas prácticas en este tipo de cultivo entre usuarios interesados.

  14. Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam

    Energy Technology Data Exchange (ETDEWEB)

    Perl, D.P.; Gajdusek, D.C.; Garruto, R.M.; Yanagihara, R.T.; Gibbs, C.J.

    1982-09-10

    Scanning electron microscopy with energy-dispersive x-ray spectrometry was used to analyze the elemental content of neurofibrillary tangle (NFT)-bearing and NFT-free neurons within the Sommer's sector (H1 region) of the hippocampus in Guamanian Chamorros with amyotrophic lateral sclerosis and parkinsonism-dementia and in neurologically normal controls. Preliminary data indicate prominent accumulation of aluminum within the nuclear region and perikaryal cytoplasm of NFT-bearing hippocampal neurons, regardless of the underlying neurological diagnosis. These findings further extend the association between intraneuronal aluminum and NFT formation and support the hypothesis that environmental factors are related to the neurodegenerative changes seen in the Chamorro population.

  15. Tangle-Free Mesh Motion for Ablation Simulations

    Science.gov (United States)

    Droba, Justin

    2016-01-01

    Problems involving mesh motion-which should not be mistakenly associated with moving mesh methods, a class of adaptive mesh redistribution techniques-are of critical importance in numerical simulations of the thermal response of melting and ablative materials. Ablation is the process by which material vaporizes or otherwise erodes due to strong heating. Accurate modeling of such materials is of the utmost importance in design of passive thermal protection systems ("heatshields") for spacecraft, the layer of the vehicle that ensures survival of crew and craft during re-entry. In an explicit mesh motion approach, a complete thermal solve is first performed. Afterwards, the thermal response is used to determine surface recession rates. These values are then used to generate boundary conditions for an a posteriori correction designed to update the location of the mesh nodes. Most often, linear elastic or biharmonic equations are used to model this material response, traditionally in a finite element framework so that complex geometries can be simulated. A simple scheme for moving the boundary nodes involves receding along the surface normals. However, for all but the simplest problem geometries, evolution in time following such a scheme will eventually bring the mesh to intersect and "tangle" with itself, inducing failure. This presentation demonstrates a comprehensive and sophisticated scheme that analyzes the local geometry of each node with help from user-provided clues to eliminate the tangle and enable simulations on a wide-class of difficult problem geometries. The method developed is demonstrated for linear elastic equations but is general enough that it may be adapted to other modeling equations. The presentation will explicate the inner workings of the tangle-free mesh motion algorithm for both two and three-dimensional meshes. It will show abstract examples of the method's success, including a verification problem that demonstrates its accuracy and

  16. Entropy in the Tangled Nature Model of evolution

    DEFF Research Database (Denmark)

    Roach, Ty N.F.; Nulton, James; Sibani, Paolo

    2017-01-01

    interpretation is supported by mathematical arguments using simulation data generated by the Tangled Nature Model (TNM), a stochastic model of evolving ecologies. We define two types of configurational entropy and study their empirical time dependence obtained from the data. Both entropy measures increase...... logarithmically with time, while the entropy per individual decreases in time, in parallel with the growth of emergent structures visible from other aspects of the simulation. We discuss the biological relevance of these entropies to describe niche space and functional space of ecosystems, as well as their use...

  17. Tangle-Free Finite Element Mesh Motion for Ablation Problems

    Science.gov (United States)

    Droba, Justin

    2016-01-01

    In numerical simulations involving boundaries that evolve in time, the primary challenge is updating the computational mesh to reflect the physical changes in the domain. In particular, the fundamental objective for any such \\mesh motion" scheme is to maintain mesh quality and suppress unphysical geometric anamolies and artifacts. External to a physical process of interest, mesh motion is an added component that determines the specifics of how to move the mesh given certain limited information from the main system. This paper develops a set of boundary conditions designed to eliminate tangling and internal collision within the context of PDE-based mesh motion (linear elasticity). These boundary conditions are developed for two- and three-dimensional meshes. The paper presents detailed algorithms for commonly occuring topological scenarios and explains how to apply them appropriately. Notably, the techniques discussed herein make use of none of the specifics of any particular formulation of mesh motion and thus are more broadly applicable. The two-dimensional algorithms are validated by an extensive verification procedure. Finally, many examples of diverse geometries in both two- and three-dimensions are shown to showcase the capabilities of the tangle-free boundary conditions.

  18. Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements

    National Research Council Canada - National Science Library

    Asuni, Ayodeji A; Boutajangout, Allal; Quartermain, David; Sigurdsson, Einar M

    2007-01-01

    .... Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype...

  19. Expression of Alzheimer-type Neurofibrillary Epitopes in Primary Rat Cortical Neurons Following Infection with Enterococcus faecalis

    Directory of Open Access Journals (Sweden)

    Robert eUnderly

    2016-01-01

    Full Text Available The neurofibrillary tau pathology and amyloid deposits seen in Alzheimer's disease (AD also have been seen in bacteria-infected brains. However, few studies have examined the role of these bacteria in the generation of tau pathology. One suggested link between infection and Alzheimer’s disease is edentulism, the complete loss of teeth. Edentulism can result from chronic periodontal disease due to infection by Enterococcus faecalis. The current study assessed the ability to generate early Alzheimer-like neurofibrillary epitopes in primary rat cortical neurons through bacterial infection by Enterococcus faecalis. Seven-day old cultured neurons were infected with Enterococcus faecalis for 24- and 48-hours. An upward molecular weight shift in tau by western blotting and increased appearance of tau reactivity in cell bodies and degenerating neurites was found in the 48-hour infection group for the antibody CP13 (phospho-Serine-202. A substantial increase in reactivity of Alz-50 was seen at 24- and 48- hours after infection. Furthermore, extensive MAP2 reactivity also was seen at 24- and 48-hours post-infection. Our preliminary findings suggest a potential link between Enterococcus faecalis infection and intracellular changes that may help facilitate early AD-like neurofibrillary pathology.

  20. Concentração e conteúdo de nutrientes em lisianto, cultivado em hidroponia, em sistema NFT = Concentration and nutrient content in lisianthus grown in a hydroponic NFT system

    Directory of Open Access Journals (Sweden)

    Fernanda Alice Antonello Londero Backes

    2008-10-01

    Full Text Available O diagnóstico nutricional é fundamental para determinar as exigências das plantas quanto aos nutrientes, de forma a se proceder a um manejo adequado, de acordo com a espécie. Assim, para determinar as concentrações e conteúdos nutricionais adequados à produção e qualidade de plantas de lisianto em cultivo hidropônico, instalou-se um experimento onde as plantas foram cultivadas em sistema NFT, em diferentes soluções nutritivas. O experimento foi conduzido, segundo delineamento experimental em blocos casualizados, em esquema fatorial 4x3, totalizando 12 tratamentos, com três repetições. Ostratamentos foram compostos de quatro cultivares (Echo Champagne, Mariachi Pure White, Balboa Yellow e Ávila Blue Rim e três soluções nutritivas (Teste, Steiner modificada e Barbosa. Foram avaliadas as concentrações e os conteúdos dos nutrientes nas folhas e conteúdos na parte aérea das plantas. As plantas cultivadas nas soluções Barbosa eTeste apresentaram resultados satisfatórios quanto às concentrações e aos conteúdos de nutrientes, enquanto a solução Steiner modificada produziu plantas com limitações nutricionais.The nutritional diagnosis is fundamental for determining plantnutrients, in order to correctly manage the nutritional requirements for each species. Thus, in order to determine the ideal nutrient amount and concentration for obtaining the best yield and quality of lisianthus grown hydroponically, an experiment was conducted inwhich the plants were grown under the NFT system in different nutrient solutions. The experiment was conducted according to a random block design arrangement in a 4x3 factorial scheme, totaling 12 treatments with three repetitions. The treatments werecomprised of four cultivars (Echo Champagne, Mariachi Pure White, Balboa Yellow and Ávila Blue Rim and three nutrient solutions (Test, modified Steiner and Barbosa. In the leaves, nutrient concentration and content were evaluated; in the aerial

  1. Homoclinic tangle of separatrix of the simple map

    Science.gov (United States)

    Pressley, Latoya; Guest, Tanzania; Johnson, Nakeisha; Punjabi, Alkesh; Ali, Halima

    2014-10-01

    The simple map is the simplest symplectic map that has the generic magnetic topology of divertor tokamaks. The generating function of the simple map is S (x , y) = x2 /2 + y2 /2-y3/3. S = 1/6 gives the separatrix surface. The scaling of safety factor on the magnetic axis, q0, with map parameter k is used to calculate the number of iterations of the simple map, Np , that is equivalent to a single toroidal circuit of the tokamak. The scaling of root mean square deviation of energy on the q95 surface with map parameter k is taken as the estimate of magnetic asymmetry to represent the magnetic perturbation from map parameter k. These data is used in the forward and backward simple maps to calculate the homoclinic tangle of the separatrix of divertor tokamaks from magnetic asymmetries. This work is supported by Grants DE-FG02-01ER54624, DE-FG02-04ER54793, and DE-FG02-07ER54937.

  2. Uso do rejeito da dessalinização de água salobra no cultivo da alface (Lactuca sativa L.) em sistema hidropônico NFT Use of the desalted wastewater for lettuce (Lactuca sativa L.) production in NFT hydroponic system

    National Research Council Canada - National Science Library

    Rafaelly Suzanye da Silva Santos; Nildo da Silva Dias; Osvaldo Nogueira de Sousa Neto; Marcelo Tavares Gurgel

    2010-01-01

    ... hidropônico NFT foi conduzido um experimento em casa de vegetação no departamento de ciências ambientais da UFERSA, em delineamento em blocos casualizados, com seis tratamentos e quatro repetições. Os...

  3. Rhizofiltration of lead using an aromatic medicinal plant Plectranthus amboinicus cultured in a hydroponic nutrient film technique (NFT) system.

    Science.gov (United States)

    Ignatius, A; Arunbabu, V; Neethu, J; Ramasamy, E V

    2014-11-01

    Heavy metal contamination of water bodies and groundwater is a major concern of the modern world. Rhizofiltration--the use of plant root system to remove/extract pollutants from wastewater--has proven advantages over conventional methods of treatment. However, commercialization of this in situ remediation technology requires a better understanding of plant-metal interactions especially on the ability of different plant species to accumulate metals at different parts of the plant system which is critical for the successful remediation of contaminated medium. Many aquatic and terrestrial plants have been reported to accumulate heavy metals when grown hydroponically. Therefore, a batch experiment with different concentrations of lead and a nutrient film technique (NFT) experiment with recycling of wastewater were employed in this study in order to investigate the rhizofiltration of lead-containing wastewater using Plectranthus amboinicus, an aromatic medicinal plant. Results show that P. amboinicus is tolerant to a wide range of lead concentrations and nutrient deficiency. The plant accumulates considerable amount of lead, particularly in the roots, and translocation to the stem and leaf was limited, indicating that the use of leaves/above-ground parts of the plant for medicinal purposes is not hindered by its ability to remove lead from the soil or water. The study also suggests that the plant can be considered for the clean-up of lead-contaminated wastewater in combination with safe biomass disposal alternatives.

  4. FT-like NFT1 gene may play a role in flower transition induced by heat accumulation in Narcissus tazetta var. chinensis.

    Science.gov (United States)

    Li, Xiao-Fang; Jia, Lin-Yan; Xu, Jing; Deng, Xin-Jie; Wang, Yang; Zhang, Wei; Zhang, Xue-Ping; Fang, Qi; Zhang, Dong-Mei; Sun, Yue; Xu, Ling

    2013-02-01

    The low-temperature flowering-response pathway, used as an inductive stimulus to induce flowering in plant species from temperate regions in response to cold temperature, has been extensively studied. However, limited information is available on the flower transition of several bulbous species, which require high temperature for flower differentiation. Narcissus tazetta var. chinensis (Chinese narcissus) exhibits a 2 year juvenile phase, and flower initiation within its bulbs occurs during summer dormancy. The genetic factors that control flower initiation are mostly unknown in Chinese narcissus. In the present study, we found that a high storage temperature is necessary for flower initiation. Flower initiation was advanced in bulbs previously exposed to extended high temperature. The heat accumulation required for flower transition was also determined. High temperature treatment rescued the low flower percentage resulting from short storage duration under natural conditions. In addition, extended high storage temperature was found to increase the flowering percentage of 2-year-old plants, which can be applied in breeding. Narcissus FLOWERING LOCUS T1 (NFT1), a homolog of the Arabidopsis thaliana gene FLOWERING LOCUS T, was isolated in this study. NFT1 transcripts were abundant during flower initiation in mature bulbs and were up-regulated by high temperature. The genetic experiments, coupled with an expression profiling assay, suggest that NFT1 possibly takes part in flower transition control in response to high temperature.

  5. Four Ways to Get Tangled Up in Russian

    Directory of Open Access Journals (Sweden)

    Maria Nordrum

    2014-11-01

    Full Text Available In this paper I will analyze the four Natural Perfectives of the simplex verb путатьipf ‘tangle up’, namely впутатьpf, спутатьpf, перепутатьpf and запутатьpf. According to Janda et al. (2013:103, “prefix variation” is a phenomenon that applies to 27% of all Russian verbs and is caused by the ability of prefixes to “focus the meanings of a simplex verb in different ways” (op. cit.:162. My question is: Is it possible to predict the choice of prefix when there is prefix variation? And, if yes: How?  My hypothesis is that the choice of prefix largely depends on the construction in which the verb appears and the semantics of its internal argument. Thus, I consider two factors in my analysis: Factor 1 Constructions and Factor 2 Semantics of the Internal Argument. My findings indicate that both factors are vital and, more specifically, that the choice of prefix for this verb to a large extent can be predicted by six tendencies that I will discuss thoroughly. I will argue that these six tendencies are of great relevance to second language learners, like myself, who often find themselves confused at the number of prefixes and, more specifically, Natural Perfectives available for a given verb. The topic of this paper has been born from a desire to gain insight with practical value in second language learning.

  6. A quantitative study of tau pathology in 11 cases of chronic traumatic encephalopathy.

    Science.gov (United States)

    Armstrong, R A; McKee, A C; Stein, T D; Alvarez, V E; Cairns, N J

    2017-02-01

    To quantify tau pathology of chronic traumatic encephalopathy (CTE) and investigate influence of dot-like lesions (DL), brain region, comorbidity and sporting career length. Densities of neurofibrillary tangles (NFT), astrocytic tangles (AT), DL, oligodendroglial inclusions (GI), neuropil threads (NT), vacuoles, neurons and enlarged neurons (EN) were measured in tau-immunoreactive sections of upper cortical laminae of frontal and temporal lobes, hippocampus (HC), amygdala and substantia nigra (SN) in 11 cases of CTE. DL were a consistent finding in CTE. Densities of NFT, NT and DL were greatest in sectors CA1 and CA2 of the HC. Densities of AT were lower than NFT, small numbers of GI were recorded in temporal lobe and low densities of vacuoles and EN were consistently present. β-Amyloid-containing neuritic plaques (NP) also occurred at low density. Densities of NFT, NT, DL and AT were greater in sulci than gyri, while vacuole density was greater in gyri. Principal components analysis (PCA) suggested that sporting career length and densities of NFT in entorhinal cortex, NT in CA2 and SN and vacuolation in the DG were significant sources of variation among cases. DL are frequent in CTE suggesting affinity with argyrophilic grain disease (AGD) and Parkinson's disease dementia (PD-Dem). Densities of AT in all regions and NT/DL in sectors CA2/4 were consistent features of CTE. The 11 cases are neuropathologically heterogeneous which may result from genetic diversity, and variation in anatomical pathways subjected to trauma. © 2016 British Neuropathological Society.

  7. Produção de alface em NFT e Floating aproveitando água salobra e o rejeito da dessalinização Lettuce production under NFT and Floating using brackish groundwater and the reject from its desalination

    Directory of Open Access Journals (Sweden)

    Alexandre Nascimento dos Santos

    2011-06-01

    Full Text Available Plantas de alface cv. Elba foram cultivadas em dois sistemas hidropônicos, Floating e NFT, com o objetivo de avaliar três tipos de água: a água salobra natural (2,47 dS m-1 obtida a partir de um poço profundo; água doce (0,11 dS m-1 produzido por dessalinização por osmose inversa, e o rejeito salino (5,15 dS m-1, um efluente do processo de dessalinização. Estas águas foram combinadas em seis tratamentos resultantes da sua utilização alternada para preparar a solução nutritiva (SN e/ou substituir as perdas por evapotranspiração (ETc. O experimento foi conduzido em casa de vegetação na região semiárida de Pernambuco, utilizando 48 unidades experimentais em blocos casualizados em esquema fatorial 6x2 com quatro repetições. O rendimento da alface (massa de matéria fresca foi maior nas condições do Floating. O uso exclusivo da água do poço profundo e do rejeito de dessalinizadores diminuiu 22,7 e 39,6% a produção de alface, respectivamente. Para uma melhor combinação de águas doces e salobras, o uso de água salobra para repor a perda por ETc pode aumentar a produção de alface em relação ao uso dessas águas para preparar a SN, estes resultados foram registrados para a água do poço profundo e o rejeito.Plants of lettuce cv. Elba were grown under two hydroponic systems, Floating and NFT, aiming to evaluate three water resources: natural brackish water (2,47 dS m-1 obtained from a deep well; fresh water (0,11 dS m-1 produced by reverse osmosis desalination; and reject brine (5,15 dS m-1, a wastewater from desalination process. These waters were combined in six treatments resulted from their alternated use to prepare nutrient solution (NS and/or replace the evapotranspiration loss (ETc. The experiment was carried out under a greenhouse condition in the semiarid region of Pernambuco State, Brazil; 48 experimental units were used for both hydroponic systems. The lettuce yield (shoot fresh matter was higher under

  8. Estratégias de uso de água salobra na produção de alface em hidroponia NFT Strategies for use of brackish water in NFT hydroponic lettuce production

    Directory of Open Access Journals (Sweden)

    Márcio S. Alves

    2011-05-01

    Full Text Available Plantas de alface crespa 'Verônica' foram cultivadas em condições hidropônicas, objetivando avaliar três diferentes estratégias de emprego de águas salobras: 1 águas salobras para reposição das perdas por evapotranspiração (ETc e água doce para o preparo da solução nutritiva (SN; 2 águas salobras para o preparo da SN e água doce para reposição da ETc; 3 águas salobras para o preparo da SN e reposição da ETc. Os níveis de salinidade da água foram obtidos pela adição de NaCl à água doce (0,27 dS m-1: 1,45; 2,51; 3,6; 5,41 e 7,5 dS m-1. O experimento foi conduzido em quatro blocos aleatorizados, com quatro repetições por tratamento. Uma estrutura de pesquisa foi construída com 72 parcelas que simulam a técnica do fluxo laminar de nutrientes (NFT. O uso de água salobra apenas para repor a ETc não produziu efeito sobre a produção da alface. Por outro lado, o uso de águas salobras para o preparo da SN e água doce para reposição da ETc, reduziu o rendimento da alface (massa de matéria fresca da parte aérea em 4,99% por (dS m-1. O rendimento foi reduzido em 7% por dS m-1 quando águas salobras foram usadas tanto para o preparo da SN quanto para reposição da ETc. Apesar da redução linear da produção da alface com o aumento da salinidade da água, sintomas depreciativos para a qualidade da alface hidropônica não foram registrados.Plants of crisphead lettuce cv. 'Verônica' were grown under hydroponic conditions aiming to evaluate three different strategies of brackish waters utilization: 1 brackish waters to replace the evapotranspiration loss (ETc and fresh water to prepare nutrient solution (NS; 2 brackish waters to prepare NS and fresh water to replace the ETc; 3 brackish waters to prepare NS and replace ETc. The levels of water salinity were obtained by addition of NaCl to fresh water (0.27 dS m-1: 1.45; 2.51; 3.6; 5.41 and 7.5 dS m-1. The experiment was conducted in randomized blocks with four

  9. Competição de cultivares de alface sob cultivo hidropônico 'NFT' em três diferentes espaçamentos Butterhead lettuce cultivars under 'NFT' hydroponic cultivation in three different spacings

    Directory of Open Access Journals (Sweden)

    Ronan Gualberto

    1999-07-01

    Full Text Available Com o objetivo de avaliar o desempenho de seis cultivares de alface do tipo lisa (Babá de Verão, Brasil 303, Elisa, Karla, Lívia e Monalisa em três espaçamentos (25 x 20, 25 x 25 e 25 x 30 cm, cultivadas em sistema hidropônico 'NFT', realizou-se um experimento na Fazenda Experimental da Universidade de Marília (SP, no período de 23 de setembro a 21 de novembro de 1997. Foram avaliadas as características comprimento de caule, produção de matéria fresca por planta e por área e produção de matéria seca da parte aérea, da raiz e total. O delineamento experimental adotado foi o de blocos casualizados, em esquema fatorial 6 x 3, com três repetições. Não houve efeito significativo da interação entre cultivares e espaçamentos. As cultivares Babá de Verão, Lívia e Elisa se destacaram pela produção de matéria fresca e matéria seca total. As cultivares Monalisa e Karla mostraram-se menos suscetíveis ao pendoamento precoce, enquanto a 'Babá de Verão' foi a mais suscetível. Não foi verificada influência significativa dos espaçamentos sobre as características estudadas, exceto para a produção por área, onde independente das cultivares utilizadas, o espaçamento 25 x 20 propiciou uma produção de 4,465 Kg/m², superior aos demais espaçamentos utilizados. Assim. Produções significativamente inferiores foram obtidas nos tratamentos 25 x 25 cm e 25 x 30 cm: 3,583 e 3,304 Kg/m², respectivamente, devido à redução no número de plantas por m².An experiment was carried out at the Experimental Farm, of Marília University, from September 23th 1997 to November 21st 1997 with the objective of evaluating the performance of six butterhead lettuce cultivars (Babá de Verão, Brasil 303, Elisa, Karla, Lívia and Monalisa in three spacings (25 x 20, 25 x 25 and 25 x 30 cm, cultivated under a hydroponic system 'NFT'. Stem length, fresh matter yield per plant and per area, and aerial part and root dry matter weight were

  10. Produção de girassol ornamental com uso de águas salobras em sistema hidropônico NFT Production of ornamental sunflower with use of brackish waters in NFT hydroponic system

    Directory of Open Access Journals (Sweden)

    Marlo P Maciel

    2012-02-01

    Full Text Available Plantas de girassol ornamental 'Sol Vermelho' foram cultivadas em hidroponia com o objetivo de avaliar o uso de águas salobras sobre seu rendimento e qualidade da inflorescência. As águas salobras foram usadas para preparar a solução nutritiva e repor as perdas por evapotranspiração. O experimento foi conduzido em delineamento inteiramente aleatorizado com cinco níveis de salinidade da água: 1,51; 2,56; 3,86 e 6,19 dS m-1, obtidos pela adição de NaCl na água doce local (0,47 dS m-1 que também foi usada como testemunha. Cada tratamento foi repetido quatro vezes e cada parcela (com quatro plantas foi construída para simular um sistema independente da técnica do fluxo laminar de nutrientes (NFT. Observou-se uma redução linear causada pelo aumento da salinidade da água sobre a altura das plantas, o diâmetro do caule e a massa da matéria seca da parte aérea. Tanto a altura da planta quanto o diâmetro do caule foram reduzidos em 3,2% e a massa de matéria seca da parte aérea foi reduzida em 5,78% (dS m-1-1, para cada acréscimo unitário da salinidade da água (dS m-1. Por outro lado, a salinidade da água não afetou o tamanho do capítulo do girassol e não foram registrados sintomas de toxicidade causados pela salinidade. Esses resultados sustentam a viabilidade técnica do uso de águas salobras para produção hidropônica de girassol ornamental.Plants of ornamental sunflower 'Sol Vermelho' were grown under hydroponic conditions aiming to evaluate the effects of use of brackish water on its yield and inflorescence (capitulum quality. The brackish waters were utilized to prepare nutrient solution and to replace water due to evapotranspiration loss. The experiment was carried out in a completely randomized experimental design with five levels of water salinity: 1.51; 2.56; 3.86 and 6.19 dS m-1, obtained by addition of NaCl to local fresh water; this fresh water (0.47 dS m-1 was also studied as control treatment. Each

  11. Neurobiological pathways to Alzheimer's disease: Amyloid-beta, TAU protein or both?

    Directory of Open Access Journals (Sweden)

    Vanessa de Jesus R. de Paula

    Full Text Available Abstract Alzheimer's disease (AD is a neurodegenerative disease characterized by progressive cognitive decline, including memory loss, behavioral and psychological symptoms and personality changes. The neuropathological hallmarks of AD are the presence of neuritic (senile plaques (NP and neurofibrillary tangles (NFT, along with neuronal loss, dystrophic neurites, and gliosis. Neuritic plaques are extracellular lesions and their main constituent is the amyloid-b42 peptide (Ab42. Neurofibrillary tangles are intracellular lesions that are mainly composed of hyperphosphorylated TAU protein. In this article, we review the major hypotheses concerning the physiopathology of AD, focusing on the b-amyloid cascade as primary events (supported by the "baptists" and cytoskeletal abnormalities secondary to the hyperphosphorylation of protein TAU (as advocated by the "Tauists". We further provide an integrative view of the physiopathology of AD.

  12. Heteroclinic tangle phenomena in nanomagnets subject to time-harmonic excitations

    Energy Technology Data Exchange (ETDEWEB)

    Serpico, C.; Quercia, A.; Perna, S. [DIETI, Università di Napoli “Federico II,” I-80125 Napoli (Italy); Bertotti, G.; Ansalone, P. [Istituto Nazionale di Ricerca Metrologica, I-10135 Torino (Italy); D' Aquino, M. [Dip. di Ingegneria, Università di Napoli “Parthenope,” I-80143 Napoli (Italy); Mayergoyz, I. [ECE Department and UMIACS, University of Maryland, College Park, Maryland 20742 (United States)

    2015-05-07

    Magnetization dynamics in uniformly magnetized nanomagnets excited by time-harmonic (AC) external fields or spin-polarized injected currents is considered. The analysis is focused on the behaviour of the AC-excited dynamics near saddle equilibria. It turns out that this dynamics has a chaotic character at moderately low power level. This chaotic and fractal nature is due to the phenomenon of heteroclinic tangle which is produced by the combined effect of AC-excitations and saddle type dynamics. By using the perturbation technique based on Melnikov function, analytical formulas for the threshold AC excitation amplitudes necessary to create the heteroclinic tangle are derived. Both the cases of AC applied fields and AC spin-polarized injected currents are treated. Then, by means of numerical simulations, we show how heteroclinic tangle is accompanied by the erosion of the safe basin around the stable regimes.

  13. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Valerie eVingtdeux

    2012-07-01

    Full Text Available Since the discovery of prion diseases, the concept that a transmissible pathogen could be a protein has emerged. As such, this transmissible protein agent can transfer its pathological mis-folded shape to the same but normally folded protein thus leading to the propagation of a disease. This idea is now extrapolate to several neurological diseases associated with protein mis-folding and aggregation, such as Alzheimer’s disease. Alzheimer’s disease (AD is a slowly developing dementing disease characterized by the coexistence of two types of lesions: the parenchymal amyloid deposits and the intraneuronal neurofibrillary tangles (NFT. Amyloid deposits are composed of amyloid-beta peptides that derive from sequential cleavages of its precursor named amyloid protein precursor. Neurofibrillary tangle is characterized by intraneuronal aggregation of abnormally modified microtubule-associated Tau proteins. A synergistic relationship between the two lesions may trigger the progression of the disease. Thus, starting in the medial temporal lobe and slowly progressing through temporal, frontal, parietal and occipital cortex, the progression of NFT is well correlated with clinical expression of the disease. However, little is known about the mechanism driving the spatiotemporal propagation of these lesions ultimately leading to the disease. A growing number of studies suggest a prion-like diffusion of amyloid deposits and NFT. In the present chapter, we will develop the current hypotheses regarding the molecular and cellular mechanisms driving the development and spreading of Alzheimer disease lesions from the window of multivesicular bodies and exosomes.

  14. The Dispersion State of Tangled Multi-Walled Carbon Nanotubes Affects Their Cytotoxicity

    Directory of Open Access Journals (Sweden)

    Chika Kuroda

    2016-11-01

    Full Text Available The medical applications of carbon nanotubes (CNTs have garnered much attention. However, evaluating the safety of CNTs remains difficult, and no consensus has been reached. Moreover, assessing the biosafety of multi-walled CNTs (MWCNTs, which can become tangled during manufacturing, is challenging because they do not readily disperse. We studied how the dispersion state of tangled MWCNTs affects their cytotoxicity, using three sonicators. Flotube 9110 (FT9110, tangled MWCNTs, were dispersed in two dispersants (fetal bovine serum and polysorbate 80 using a new type of sonicator (PR-1 and two conventional sonicators. The size and cytotoxicity of the dispersed FT9110 were measured using the BEAS-2B human bronchial epithelial cell line. The PR-1 dispersed the FT9110 to agglomerates <200 nm in diameter; FT9110 dispersed with the PR-1 did not show cytotoxicity regardless of dispersant. The other sonicators dispersed the FT9110 to particles >1000 nm in diameter, and cytotoxicity depended on the dispersant. We found that excluding cells adhered to agglomerated FT9110 before evaluating cytotoxicity can lead to false-positive results. The PR-1 sonicator dispersed tangled FT9110 to many single fibers, which showed lower cytotoxicity than conventionally-sonicated MWCNTs. We suggest that dispersion state should be accounted for when evaluating the cytotoxicity of MWCNTs.

  15. Rapunzel Loves Merida: Melodramatic Expressions of Lesbian Girlhood and Teen Romance in Tangled, Brave, and Femslash.

    Science.gov (United States)

    Kapurch, Katie

    2015-01-01

    This article explores the melodramatic expression of lesbian girlhood and teen romance in Disney's Tangled (2010) and Disney Pixar's Brave (2012), as well as "Meripunzel" femslash, fan-authored romantic pairings of the animations' female protagonists. First, Anne Sexton's poem, "Rapunzel," offers a literary precedent for exploring lesbian themes in the fairy tale. The next section shows how Tangled and Brave invoke the narrative conventions of the family melodrama. This generic association reveals the films' uses of rhetoric familiar to youth coming-out narratives, as well as other visual and aural coding suggestive of queer styles. The last section shows how Meripunzel femslash taps into the films' existing melodramatic narrative forms and visual aesthetics, rehearsing their coming-out rhetoric while addressing the pleasures of and problems facing lesbian teen romance. I conclude by problematizing the often conventional expressions of lesbian girlhood in femslash, ultimately arguing for their empowering potential, especially as they indicate revised definitions of "princess."

  16. Influence of Water Quality on Cholesterol-Induced Tau Pathology: Preliminary Data

    Directory of Open Access Journals (Sweden)

    D. Larry Sparks

    2011-01-01

    Full Text Available The studies employed the cholesterol-fed rabbit model of Alzheimer's disease (AD to investigate the relationship between AD-like neurofibrillary tangle (NFT neuropathology and tau protein levels as the main component of NFT. We measured brain and plasma tau levels and semiquantified NFT-like neuropathology in cholesterol-fed rabbits administered drinking water of varying quality (distilled, tap, and distilled+copper compared to animals receiving normal chow and local tap water. Total tau levels in plasma were increased in all cholesterol-fed rabbits compared to animals on normal chow, regardless of quality of water. In contrast, increased tau in brain and increased AT8 immunoreactive NFT-like lesions were greatest in cholesterol-fed rabbits administered distilled water. A substantial decrease in brain tau and incidence and density of AT8 immunoreactive NFT-like lesions occurred in cholesterol-fed rabbits administered copper water, and an even greater decrease was observed in cholesterol-fed animals on local tap water. These studies suggest the possibility that circulating tau could be the source of the tau accumulating in the brain.

  17. Characterization of TauC3 antibody and demonstration of its potential to block tau propagation.

    Directory of Open Access Journals (Sweden)

    Samantha B Nicholls

    Full Text Available The spread of neurofibrillary tangle (NFT pathology through the human brain is a hallmark of Alzheimer's disease (AD, which is thought to be caused by the propagation of "seeding" competent soluble misfolded tau. "TauC3", a C-terminally truncated form of tau that is generated by caspase-3 cleavage at D421, has previously been observed in NFTs and has been implicated in tau toxicity. Here we show that TauC3 is found in the seeding competent high molecular weight (HMW protein fraction of human AD brain. Using a specific TauC3 antibody, we were able to substantially block the HMW tau seeding activity of human AD brain extracts in an in vitro tau seeding FRET assay. We propose that TauC3 could contribute to the templated tau misfolding that leads to NFT spread in AD brains.

  18. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits.

    Directory of Open Access Journals (Sweden)

    Smita Majumder

    Full Text Available Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ. However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

  19. Effect of fermented sea tangle on the alcohol dehydrogenase and acetaldehyde dehydrogenase in Saccharomyces cerevisiae.

    Science.gov (United States)

    Cha, Jae-Young; Jeong, Jae-Jun; Yang, Hyun-Ju; Lee, Bae-Jin; Cho, Young-Su

    2011-08-01

    Sea tangle, a kind of brown seaweed, was fermented with Lactobacillus brevis BJ-20. The gamma-aminobutyric acid (GABA) content in fermented sea tangle (FST) was 5.56% (w/w) and GABA in total free amino acid of FST was 49.5%. The effect of FST on the enzyme activities and mRNA protein expression of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) involved in alcohol metabolism in Saccharomyces cerevisiae was investigated. Yeast was cultured in YPD medium supplemented with different concentrations of FST powder [0, 0.4, 0.8, and 1.0% (w/v)] for 18 h. FST had no cytotoxic effect on the yeast growth. The highest activities and protein expressions of ADH and ALDH from the cell-free extracts of S. cerevisiae were evident with the 0.4% and 0.8% (w/v) FST-supplemented concentrations, respectively. The highest concentrations of GABA as well as minerals (Zn, Ca, and Mg) were found in the cell-free extracts of S. cerevisiae cultured in medium supplemented with 0.4% (w/v) FST. The levels of GABA, Zn, Ca, and Mg in S. cerevisiae were strongly correlated with the enzyme activities of ADH and ALDH in yeast. These results indicate that FST can enhance the enzyme activities and protein expression of ADH and ALDH in S. cerevisiae.

  20. OpenNFT: An open-source Python/Matlab framework for real-time fMRI neurofeedback training based on activity, connectivity and multivariate pattern analysis.

    Science.gov (United States)

    Koush, Yury; Ashburner, John; Prilepin, Evgeny; Sladky, Ronald; Zeidman, Peter; Bibikov, Sergei; Scharnowski, Frank; Nikonorov, Artem; De Ville, Dimitri Van

    2017-08-01

    Neurofeedback based on real-time functional magnetic resonance imaging (rt-fMRI) is a novel and rapidly developing research field. It allows for training of voluntary control over localized brain activity and connectivity and has demonstrated promising clinical applications. Because of the rapid technical developments of MRI techniques and the availability of high-performance computing, new methodological advances in rt-fMRI neurofeedback become possible. Here we outline the core components of a novel open-source neurofeedback framework, termed Open NeuroFeedback Training (OpenNFT), which efficiently integrates these new developments. This framework is implemented using Python and Matlab source code to allow for diverse functionality, high modularity, and rapid extendibility of the software depending on the user's needs. In addition, it provides an easy interface to the functionality of Statistical Parametric Mapping (SPM) that is also open-source and one of the most widely used fMRI data analysis software. We demonstrate the functionality of our new framework by describing case studies that include neurofeedback protocols based on brain activity levels, effective connectivity models, and pattern classification approaches. This open-source initiative provides a suitable framework to actively engage in the development of novel neurofeedback approaches, so that local methodological developments can be easily made accessible to a wider range of users. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Holocene pollen and sediment record from the tangle lakes area, central Alaska

    Science.gov (United States)

    Ager, Thomas A.; Sims, John D.

    1981-01-01

    Pollen and sediments have been analyzed from a 5.5 meter‐length core of lacustrine sediments from Tangle Lakes, in the Gulkana Upland south of the Alaska Range (63 ° 01 ‘ 46”; N. latitude, 146° 03 ‘ 48 “ W. longitude). Radiocarbon ages indicate that the core spans the last 4700 years. The core sediments are sandy silt and silty clay; the core shows distinct rhythmic laminations in the lower 398 cm. The laminae appear to be normally graded; peat fibers and macerated plant debris are more abundant near the tops of the laminae. Six volcanic‐ash layers are present in the upper 110 cm of the core.Present‐day vegetation of the Tangle Lakes area is mesic shrub tundra and open spruce woodland, with scattered patches of shrub willow (Salix), balsam poplar (P. balsamifera), spruce (Picea), paper birch (Betula papyrifera), and alder (Alnus). Pollen analysis of 27 core samples suggests that this vegetation type has persisted throughout the past 4700 years, except for an apparently substantial increase in Picea beginning about 3500 years B.P. Percentages of Picea pollen are very low (generally 1–3 percent) in the lower 2 meters of core (ca. 4700 to 3500 years B.P.), but rise to 13–18 percent in the upper 3.4 meters (ca. 3500 years B.P. to present). Previously reported data from this area indicate that Picea trees initially arrived in the Tangle Lakes area about 9100 years B.P., at least 2.5 to 3 thousand years after deglaciation of the region. The present investigation suggests that Picea trees became locally scarce or died out sometime after about 9000 years B.P. but before 4700 years B.P., then reinvaded the area about 3500 years B.P. If this extrapolated age for the Picea reinvasion is accurate it suggests that local expansion of the Picea population coincides with the onset of a Neoglacial interval of cooler, moister climate. This is an unexpected result, because intervals of cooler climate generally coincide with lowering of the altitudinal limit of

  2. 3D printed cat tongue is a self-cleaning, tangle-teasing brush

    Science.gov (United States)

    Noel, Alexis; Hu, David

    A cat's tongue is covered in an array of spines called papillae. These spines are thought to be used in grooming and rasping meat from bones of prey, although no mechanism has been given. We use high-speed video to film a cat grooming. We show that the spines on the tongue act as low pass filters for tangles in hair. The tongue itself is highly elastic, while the spines are rigid. We 3D print a cat tongue mimic and show that the nonlinear force applied by the spines helps to increase efficacy of grooming. The tongue also provides frictional anisotropy with backward-facing spines, allowing for self-cleaning properties post-groom.

  3. Vortex arrays and ciliary tangles underlie the feeding-swimming tradeoff in starfish larvae

    CERN Document Server

    Gilpin, William; Prakash, Manu

    2016-01-01

    Many marine invertebrates have larval stages covered in linear arrays of beating cilia, which propel the animal while simultaneously entraining planktonic prey. These bands are strongly conserved across taxa spanning four major superphyla, and they are responsible for the unusual morphologies of many invertebrates. However, few studies have investigated their underlying hydrodynamics. Here, we study the ciliary bands of starfish larvae, and discover a beautiful pattern of slowly-evolving vortices that surrounds the swimming animals. Closer inspection of the bands reveals unusual ciliary "tangles" analogous to topological defects that break-up and re-form as the animal adjusts its swimming stroke. Quantitative experiments and modeling suggest that these vortices create a physical tradeoff between feeding and swimming, which manifests as distinct flow patterns or "eigenstrokes" representing each behavior---potentially implicating neuronal control of cilia. This quantitative interplay between larval form and hyd...

  4. Evolution and non-equilibrium physics: A study of the Tangled Nature Model

    Science.gov (United States)

    Becker, Nikolaj; Sibani, Paolo

    2014-01-01

    We argue that the stochastic dynamics of interacting agents which replicate, mutate and die constitutes a non-equilibrium physical process akin to aging in complex materials. Specifically, our study uses extensive computer simulations of the Tangled Nature Model (TNM) of biological evolution to show that punctuated equilibria successively generated by the model's dynamics have increasing entropy and are separated by increasing entropic barriers. We further show that these states are organized in a hierarchy and that limiting the values of possible interactions to a finite interval leads to stationary fluctuations within a component of the latter. A coarse-grained description based on the temporal statistics of quakes, the events leading from one component of the hierarchy to the next, accounts for the logarithmic growth of the population and the decaying rate of change of macroscopic variables. Finally, we question the role of fitness in large-scale evolution models and speculate on the possible evolutionary role of rejuvenation and memory effects.

  5. Tangled Narratives and Wicked Problems: A Complex Case of Positioning and Politics in a Diverse School Community

    Science.gov (United States)

    Nguyen, Thu Suong Thi; Scribner, Samantha M. Paredes; Crow, Gary M.

    2012-01-01

    The case of Allen Elementary School presents tangled narratives and wicked problems describing the multidimensionality of school community work. Using multiple converging and diverging vignettes, the case points to the distinctiveness of individual experience in schools; the ways institutionalized organizational narratives become cultural…

  6. Vortex arrays and ciliary tangles underlie the feeding-swimming tradeoff in starfish larvae

    Science.gov (United States)

    Gilpin, William; Prakash, Vivek N.; Prakash, Manu

    2016-11-01

    Many marine invertebrates have larval stages covered in linear arrays of beating cilia, which propel the animal while simultaneously entraining planktonic prey. These bands are strongly conserved across taxa spanning four major superphyla, and they are responsible for the unusual morphologies of many invertebrates. However, few studies have investigated their underlying hydrodynamics. Here, we study the ciliary bands of starfish larvae, and discover a beautiful pattern of slowly-evolving vortices that surrounds the swimming animals. Closer inspection of the bands reveals unusual ciliary "tangles" analogous to topological defects that break-up and re-form as the animal adjusts its swimming stroke. Quantitative experiments and modeling demonstrate that these vortices create a physical tradeoff between feeding and swimming in heterogenous environments, which manifests as distinct flow patterns or "eigenstrokes" representing each behavior-potentially implicating neuronal control of cilia. This quantitative interplay between larval form and hydrodynamic function generalizes to other invertebrates, and illustrates the potential effects of active boundary conditions in other biological and synthetic systems.

  7. Vortex arrays and ciliary tangles underlie the feeding-swimming trade-off in starfish larvae

    Science.gov (United States)

    Gilpin, William; Prakash, Vivek N.; Prakash, Manu

    2017-04-01

    Many marine invertebrates have larval stages covered in linear arrays of beating cilia, which propel the animal while simultaneously entraining planktonic prey. These bands are strongly conserved across taxa spanning four major superphyla, and they are responsible for the unusual morphologies of many invertebrate larvae. However, few studies have investigated their underlying hydrodynamics. Here, we study the ciliary bands of starfish larvae, and discover a beautiful pattern of slowly evolving vortices that surrounds the swimming animals. Closer inspection of the bands reveals unusual ciliary `tangles' analogous to topological defects that break up and re-form as the animal adjusts its swimming stroke. Quantitative experiments and modelling demonstrate that these vortices create a physical trade-off between feeding and swimming in heterogeneous environments, which manifests as distinct flow patterns or `eigenstrokes' representing each behaviour--potentially implicating neuronal control of cilia. This quantitative interplay between larval form and hydrodynamic function may generalize to other invertebrates with ciliary bands, and illustrates the potential effects of active boundary conditions in other biological and synthetic systems.

  8. Continuous variable tangle, monogamy inequality, and entanglement sharing in Gaussian states of continuous variable systems

    Energy Technology Data Exchange (ETDEWEB)

    Adesso, Gerardo; Illuminati, Fabrizio [Dipartimento di Fisica ' E R Caianiello' , Universita degli Studi di Salerno (Italy); CNISM and CNR-Coherentia, Gruppo di Salerno (Italy); and INFN Sezione di Napoli-Gruppo Collegato di Salerno (Italy); Via S Allende, 84081 Baronissi, SA (Italy)

    2006-01-15

    For continuous-variable (CV) systems, we introduce a measure of entanglement, the CV tangle (contangle), with the purpose of quantifying the distributed (shared) entanglement in multimode, multipartite Gaussian states. This is achieved by a proper convex-roof extension of the squared logarithmic negativity. We prove that the contangle satisfies the Coffman-Kundu-Wootters monogamy inequality in all three-mode Gaussian states, and in all fully symmetric N-mode Gaussian states, for arbitrary N. For three-mode pure states, we prove that the residual entanglement is a genuine tripartite entanglement monotone under Gaussian local operations and classical communication. We show that pure, symmetric three-mode Gaussian states allow a promiscuous entanglement sharing, having both maximum tripartite residual entanglement and maximum couplewise entanglement between any pair of modes. These states are thus simultaneous CV analogues of both the GHZ and the W states of three qubits: in CV systems monogamy does not prevent promiscuity, and the inequivalence between different classes of maximally entangled states, holding for systems of three or more qubits, is removed.

  9. Evaluation of 8-week body weight control program including sea tangle (Laminaria japonica) supplementation in Korean female college students

    OpenAIRE

    You, Jeong Soon; Sung, Min Jung; Chang, Kyung Ja

    2009-01-01

    This study was conducted to evaluate the effects of a body weight control program with supplementation of sea tangle (20 g/day) on 22 female college students. The contents of the program for 8 weeks contained diet therapy, exercise and behavioral modification through nutrition education. Body composition, dietary habit scores, serum lipid profiles, daily nutrient intakes and the quality of life were assessed at the beginning and at the end of the program. Average age of subjects and height we...

  10. Efeito da concentração da solução nutritiva no crescimento da alface em cultivo hidropônico-sistema NFT Effects of the concentration of nutrient solution on lettuce growth in hydroponics-NFT system

    Directory of Open Access Journals (Sweden)

    Nilton Nélio Cometti

    2008-06-01

    Full Text Available Foi avaliado o crescimento da alface (Lactuca sativa L. cv 'Vera' em um sistema hidropônico NFT com diferentes concentrações da solução nutritiva. O experimento foi realizado em casa de vegetação de abril a maio de 2000, na UFRRJ, Seropédica (RJ. Os tratamentos constaram de quatro soluções nutritivas, diferentes quanto à concentração de macronutrientes: 100; 50; 25 e 12,5% da concentração original proposta por Furlani (1997. A produção de massa seca (parte comercial em solução nutritiva a 50% da concentração original, e condutividade elétrica em torno de 0,98 dS m-1, foi semelhante à solução a 100% da força iônica. As produções obtidas com 100 e 50% da força iônica estiveram dentro da faixa de 90% da produção máxima, calculada em 75±1% da força iônica da solução nutritiva, simulada por equação de regressão. Entretanto, o uso de concentrações menores resultou em redução no crescimento de 50% com a solução a 25% e 80% com a solução a 12,5% da força iônica, nas condições de luz e temperatura em que o experimento foi conduzido. A redução da concentração da solução nutritiva permite uma economia de pelo menos 50% no custo da solução nutritiva básica, reduzindo-se a solução inicial para 1,00 dS m-1, sem comprometer a produtividade.The growth of lettuce (Lactuca sativa L. cv 'Vera' was evaluated in a NFT hydroponic system with different nutrient solution concentrations. An experiment was carried out in a greenhouse from April to May, 2000 in Rio de Janeiro State, Brazil. Four treatments were used differing in macro nutrient concentration: 100; 50; 25 and 12.5% of the original concentration of the solution proposed by Furlani (1997. Using 50% of the original concentration with electric conductivity around 0,98 dS m-1, plants produced the same shoot dry mass as using 100% of the ionic strength. In this trial, the phytomass yield using 100 and 50% of the ionic strength was within the range

  11. [18F]-T807 tauopathy PET imaging in chronic traumatic encephalopathy [v1; ref status: indexed, http://f1000r.es/4fb

    Directory of Open Access Journals (Sweden)

    Sam Gandy

    2014-09-01

    Full Text Available A new molecular ligand for positron emission tomography (PET of the human brain, [18F]-T807, is under investigation for the antemortem detection of pathological neurofibrillary aggregates, which are evidence of neurofibrillary tangle (NFT diseases, also known as tauopathies. Repetitive mild traumatic brain injuries in athletes and battlefield veterans are associated with one such tauopathy, known as chronic traumatic encephalopathy (CTE. In a recent case report, a former NFL player with clinically probable CTE and a concurrent Progressive Supranuclear Palsy (PSP –like syndrome was studied using [18F]-T807. The interpretation of this player’s [18F]-T807 PET imaging was complicated by the overlap of tracer uptake in brain regions involved in CTE and PSP with regions associated with either nonspecific [18F]-T807 ligand binding or “aging-associated” binding of [18F]-T807 to authentic tauopathy known to be associated with aging and disease severity (i.e., NFT in the mesial temporal lobe. The implications of these data for the utility of [18F]-T807 in the pre-mortem detection of CTE are summarized.

  12. Micro-evolution of toxicant tolerance: from single genes to the genome's tangled bank.

    Science.gov (United States)

    van Straalen, Nico M; Janssens, Thierry K S; Roelofs, Dick

    2011-05-01

    abandoned. These data, added to a genome-wide gene expression profiling study reported earlier shows that evolution of tolerance takes place in a complicated molecular network, not unlike an internal tangled bank. © The Author(s) 2011. This article is published with open access at Springerlink.com

  13. The Visual Metaphor of Disability in Sarah Leavitt's Graphic Memoir Tangles: A story about alzheimer's, my mother, and me

    Directory of Open Access Journals (Sweden)

    Renata Lucena Dalmaso

    2015-01-01

    Borrowing George Lakoff and Mark Johnson’s Conceptual Metaphor theory, and its implications for the study of visual metaphors, this article seeks to investigate the representation of the disabled body in the graphic memoir Tangles: A Story about Alzheimer’s, My Mother, and Me (2012, by Sarah Leavitt. The genre of comics, as a cross-discursive medium, is prolific in the use of visual metaphor as a narrative technique and Leavitt’s graphic memoir, in particular, employs visual metaphor in the depiction of her mother’s experience of Alzheimer’s, as someone slowly distancing herself from her family.

  14. Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old.

    Science.gov (United States)

    Sinka, Lidia; Kövari, Enikö; Gold, Gabriel; Hof, Patrick R; Herrmann, François R; Bouras, Constantin; Giannakopoulos, Panteleimon

    2010-12-01

    The relative contributions of Alzheimer disease (AD) and vascular lesion burden to the occurrence of cognitive decline are more difficult to define in the oldest-old than they are in younger cohorts. To address this issue, we examined 93 prospectively documented autopsy cases from 90 to 103 years with various degrees of AD lesions, lacunes, and microvascular pathology. Cognitive assessment was performed prospectively using the Clinical Dementia Rating scale. Neuropathologic evaluation included the Braak neurofibrillary tangle (NFT) and β-amyloid (Aβ) protein deposition staging and bilateral semiquantitative assessment of vascular lesions. Statistics included regression models and receiver operating characteristic analyses. Braak NFTs, Aβ deposition, and cortical microinfarcts (CMIs) predicted 30% of Clinical Dementia Rating variability and 49% of the presence of dementia. Braak NFT and CMI thresholds yielded 0.82 sensitivity, 0.91 specificity, and 0.84 correct classification rates for dementia. Using these threshold values, we could distinguish 3 groups of demented cases and propose criteria for neuropathologic definition of mixed dementia, pure vascular dementia, and AD in very old age. Braak NFT staging and severity of CMI allow for defining most of demented cases in the oldest-old. Most importantly, single cutoff scores for these variables that could be used in the future to formulate neuropathologic criteria for mixed dementia in this age group were identified.

  15. Aged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease.

    Science.gov (United States)

    Edler, Melissa K; Sherwood, Chet C; Meindl, Richard S; Hopkins, William D; Ely, John J; Erwin, Joseph M; Mufson, Elliott J; Hof, Patrick R; Raghanti, Mary Ann

    2017-11-01

    Alzheimer's disease (AD) is a uniquely human brain disorder characterized by the accumulation of amyloid-beta protein (Aβ) into extracellular plaques, neurofibrillary tangles (NFT) made from intracellular, abnormally phosphorylated tau, and selective neuronal loss. We analyzed a large group of aged chimpanzees (n = 20, age 37-62 years) for evidence of Aβ and tau lesions in brain regions affected by AD in humans. Aβ was observed in plaques and blood vessels, and tau lesions were found in the form of pretangles, NFT, and tau-immunoreactive neuritic clusters. Aβ deposition was higher in vessels than in plaques and correlated with increases in tau lesions, suggesting that amyloid build-up in the brain's microvasculature precedes plaque formation in chimpanzees. Age was correlated to greater volumes of Aβ plaques and vessels. Tangle pathology was observed in individuals that exhibited plaques and moderate or severe cerebral amyloid angiopathy, a condition in which amyloid accumulates in the brain's vasculature. Amyloid and tau pathology in aged chimpanzees suggests these AD lesions are not specific to the human brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Uso do rejeito da dessalinização de água salobra no cultivo da alface (Lactuca sativa L. em sistema hidropônico NFT Use of the desalted wastewater for lettuce (Lactuca sativa L. production in NFT hydroponic system

    Directory of Open Access Journals (Sweden)

    Rafaelly Suzanye da Silva Santos

    2010-08-01

    Full Text Available A dessalinização por osmose reversa tem sido bastante utilizada para o tratamento de água salobra, possibilitando a sua utilização para o consumo humano, especialmente em regiões semiáridas. Esse processo tem um fator limitante que é a produção de um rejeito de água com alta salinidade. Com o objetivo de avaliar os efeitos da utilização de água de rejeito da dessalinização no cultivo de alface cultivar Vera (Lactuca sativa L. em sistema hidropônico NFT foi conduzido um experimento em casa de vegetação no departamento de ciências ambientais da UFERSA, em delineamento em blocos casualizados, com seis tratamentos e quatro repetições. Os níveis de salinidade da água entre os tratamentos foram obtidos com, ou sem a necessidade de diluição da água de rejeito da dessalinização acrescido da solução nutritiva com salinidade de 1 dS m-1 (100% de água potável de abastecimento - 1,4 dS m-1; 85% abastecimento e 15% água de rejeito - 1,9 dS m-1; 75 % água de rejeito + 25 % água de abastecimento - 2,7 dS m-1; 50% água de rejeito e 50% água de abastecimento - 3,8 dS m-1; 25 % água de rejeito e 75 % água de abastecimento - 4,9 dS m-1 e água de rejeito coletada no dessalinizador - 5,5 dS m-1. Os parâmetros analisados foram área foliar, diâmetro do caule, número de folhas, peso de matéria fresca e o peso de matéria seca. Todas as variáveis estudadas foram influenciadas negativamente de forma linear pelo efeito da concentração de sais na água de irrigação, sendo que a área foliar e a matéria fresca da parte aérea são as que melhor representam a sensibilidade ao estresse salino na cultivar estudada, tendo a produção em termos de matéria fresca uma redução de 94,83%, ao se elevar a CEa de 1,4 a 5,5 dS m-1.The desalination process by reverse osmosis was used for the treatment of brackish water, making possible the usage human consume in semiarid zones. This process has a limiting factor: it produces

  17. Oxidative Stress and Metabolic Syndrome: Cause or Consequence of Alzheimer's Disease?

    Directory of Open Access Journals (Sweden)

    Diana Luque-Contreras

    2014-01-01

    Full Text Available Alzheimer’s disease (AD is a major neurodegenerative disease affecting the elderly. Clinically, it is characterized by a progressive loss of memory and cognitive function. Neuropathologically, it is characterized by the presence of extracellular β-amyloid (Aβ deposited as neuritic plaques (NP and neurofibrillary tangles (NFT made of abnormal and hyperphosphorylated tau protein. These lesions are capable of generating the neuronal damage that leads to cell death and cognitive failure through the generation of reactive oxygen species (ROS. Evidence indicates the critical role of Aβ metabolism in prompting the oxidative stress observed in AD patients. However, it has also been proposed that oxidative damage precedes the onset of clinical and pathological AD symptoms, including amyloid-β deposition, neurofibrillary tangle formation, vascular malfunction, metabolic syndrome, and cognitive decline. This paper provides a brief description of the three main proteins associated with the development of the disease (Aβ, tau, and ApoE and describes their role in the generation of oxidative stress. Finally, we describe the mitochondrial alterations that are generated by Aβ and examine the relationship of vascular damage which is a potential prognostic tool of metabolic syndrome. In addition, new therapeutic approaches targeting ROS sources and metabolic support were reported.

  18. The human pineal gland in aging and Alzheimer's disease: patterns of cytoskeletal antigen immunoreactivity.

    Science.gov (United States)

    Pardo, C A; Martin, L J; Troncoso, J C; Price, D L

    1990-01-01

    Patients with Alzheimer's disease (AD) and some aged controls may have diminished functions of the pineal gland. In this immunocytochemical study, we stained pineal glands from cases of AD and young and aged controls for cytoskeletal elements and amyloid. We found no evidence of neurofibrillary tangles (NFT) or the accumulation of neurofilaments, tau, A68, or beta/A4 amyloid deposition in pinealocytes or associated structures in cases of AD or controls. In both AD and controls, we observed dense immunoreactivity for phosphorylated neurofilaments in marginal plexuses associated with processes of pinealocytes, boutons, and knob-like endings. The accumulation of phosphorylated neurofilaments in the processes of pinealocytes appears to be a normal morphological characteristic of the pineal gland and may not represent a pathological change.

  19. Evaluation of 8-week body weight control program including sea tangle (Laminaria japonica) supplementation in Korean female college students.

    Science.gov (United States)

    You, Jeong Soon; Sung, Min Jung; Chang, Kyung Ja

    2009-01-01

    This study was conducted to evaluate the effects of a body weight control program with supplementation of sea tangle (20 g/day) on 22 female college students. The contents of the program for 8 weeks contained diet therapy, exercise and behavioral modification through nutrition education. Body composition, dietary habit scores, serum lipid profiles, daily nutrient intakes and the quality of life were assessed at the beginning and at the end of the program. Average age of subjects and height were 20.8 years and 161.9 cm, respectively. After 8 weeks, there were significant reductions in body weight, body fat mass, percent body fat, waist-hip ratio and BMI. The dietary habit score such as a balanced diet, regularity of mealtime, overeating, eating while watching TV or using the computer and eating salty food were increased significantly. Serum lipid levels such as total cholesterol level, LDL-cholesterol level and triglyceride level were decreased but not significantly. There were decreases in intake of energy, protein and fat and increases in intakes of dietary fiber, folic acid, calcium and potassium from the beginning to the end of the program. There were significant improvements on subcomponents of quality of life; physical functioning, general-health and vitality. The limitation of this study was the fact that there was no control group, but an overall evaluation suggests the 8-week body weight control program consisting of diet therapy, exercise and behavioral modification with supplementation of sea tangle would be helpful to improve the body composition, dietary habits, daily nutrient intakes and quality of life in Korean female college students.

  20. Desempenho de cultivares de alface crespa em dois ambientes de cultivo em sistema hidropônico Performance of lettuce cultivars grown in two environments, in the NFT hydroponic system

    Directory of Open Access Journals (Sweden)

    SF Blat

    2011-03-01

    Full Text Available Este trabalho foi desenvolvido em Ribeirão Preto-SP, de 06/02 a 07/04 de 2006. O objetivo foi avaliar o desempenho de cinco cultivares de alface (Pira Roxa, Belíssima, Locarno, Crespona Gigante e Verônica em dois ambientes de cultivo (casa de vegetação climatizada e não climatizada em sistema hidropônico NFT. O delineamento experimental foi em blocos casualizados para cada ambiente com três repetições sendo cinco cultivares. Os ambientes foram comparados por meio de análise conjunta. Avaliaram-se a massa fresca e seca da parte aérea, massas fresca e seca do caule, massa fresca e seca da raiz, número de folhas maiores que 10 cm e número total de folhas. Não houve efeito significativo da interação cultivares e ambientes, demonstrando que as cultivares tiveram comportamento similar em ambos os ambientes.This research was carried out in Ribeirão Preto, São Paulo State, Brazil, from February to April, 2006. The performance of five lettuce cultivars (Pira Roxa, Belíssima, Locarno, Crespona Gigante and Verônica was evaluated, growing the plants in two environments (conventional and acclimatized greenhouse in hydroponic system NFT. A randomized-block experimental design was used for each environment, with three replications and five cultivars. The environments were compared through joint analysis. Evaluations were done for fresh and dry mater of the aboveground part, stem, and roots; number of leaves larger than 10 cm and total number of leaves. The cultivars Crespona Gigante and Verônica were prominent with regard to green and dry mass of the aboveground part, leaves, and roots, as well as to the number of leaves larger than 10 cm. The interaction cultivar x environment was not significant, demonstrating that the cultivars had similar behavior in both environments.

  1. Production de minitubercules de pomme de terre par hydroponie: évaluation d'un système combinant les techniques NFT et Gravel Culture pour deux types de solutions nutritives

    Directory of Open Access Journals (Sweden)

    Rolot J.L.

    2002-01-01

    Full Text Available Potato minituber production through hydropony: assessment of a system combining the NFT and Gravel Culture techniques for two types of nutrient solutions. The potato minituber production is the classical intermediate stage enabling field use of potato materials with an in vitro origin. This production of minitubers may be achieved through various techniques. Most often however they are based upon bedding vitroplantlets or vitroplantlets cuttings in an organic substratum which is disinfected or not. The soilless culture of plants stemming from vitrotubers to produce minitubers with a superior health quality was tested within a hydroponic system. Two types of nutrient solutions were compared: a nitrogen rich one (NPK, mg/l, 180-40-300 and a phosphorus rich one (NPK, mg/l, 60-150-300. In order to initiate the cultures, presprouting microtubers of several varieties (Bintje, Kennebec, Spunta, Saturna, Desiree and Gasore were used. Multiplication rates ranged between 13.2 (Saturna and 3.8 (Kennebec minitubers with a grade higher than 10 mm (more than 1.5 g. As the selected density of the plants was 59 plants per square metre, the yield per square metre varied from 224 to 779 minitubers with a grade higher than 10 mm. The obtained number of minitubers depended especially on the variety. The phosphorus enrichment of the nutrient solution induced an increased number of minitubers produced with a grade higher than 15 mm (more than 5 g. The health state of the produced tubers was excellent.

  2. TEMPERATURA DO AR NO INTERIOR DO CANAL DE CULTIVO E CRESCIMENTO DA ALFACE EM FUNÇÃO DO MATERIAL DE COBERTURA DA MESA DE CULTIVO HIDROPÔNICO - NFT

    Directory of Open Access Journals (Sweden)

    MATTOS KAREN MARIA DA COSTA

    2001-01-01

    Full Text Available Estudou-se o efeito de diferentes tipos de material de cobertura de mesas de cultivo hidropônico-NFT na temperatura do interior das canaletas e no crescimento da alface (Lactuca sativa L., cv. Verônica. Em comparação ao tratamento-controle (tubos de polipropileno, utilizaram-se mantas de polietileno dupla face (branco e preto e de Tetra-Pak®. O experimento foi realizado no Núcleo Experimental de Campinas, do Instituto Agronômico (22°54'S, 47°05'W, 674 m de altitude, usando-se mesas de cultivo com 24 m de comprimento, dividida em quatro blocos simétricos com os tratamentos distribuídos ao acaso. Sessenta termopares foram instalados no interior dos tubos para avaliar a temperatura interna do ar; armazenaram-se os sinais em um datalogger. Os valores medidos no interior dos tubos foram sempre superiores aos externos. Entretanto, nos tubos protegidos com Tetra-Pak®, os dados da temperatura interna do ar foram sempre de menor magnitude e, os de massa fresca de plantas de alface, superiores aos demais tratamentos. Essas diferenças foram estatisticamente significativas pelo teste de Tukey ao nível de 5%. No período noturno, nenhuma diferença de comportamento foi obtida entre os três tratamentos usados.

  3. Medline Plus

    Full Text Available In a person with Alzheimer disease, neurofibrillary tangles and plaques develop causing both structural and chemical problems in the brain. Alzheimer disease appears to disconnect ...

  4. Primary age-related tauopathy (PART): a common pathology associated with human aging.

    Science.gov (United States)

    Crary, John F; Trojanowski, John Q; Schneider, Julie A; Abisambra, Jose F; Abner, Erin L; Alafuzoff, Irina; Arnold, Steven E; Attems, Johannes; Beach, Thomas G; Bigio, Eileen H; Cairns, Nigel J; Dickson, Dennis W; Gearing, Marla; Grinberg, Lea T; Hof, Patrick R; Hyman, Bradley T; Jellinger, Kurt; Jicha, Gregory A; Kovacs, Gabor G; Knopman, David S; Kofler, Julia; Kukull, Walter A; Mackenzie, Ian R; Masliah, Eliezer; McKee, Ann; Montine, Thomas J; Murray, Melissa E; Neltner, Janna H; Santa-Maria, Ismael; Seeley, William W; Serrano-Pozo, Alberto; Shelanski, Michael L; Stein, Thor; Takao, Masaki; Thal, Dietmar R; Toledo, Jonathan B; Troncoso, Juan C; Vonsattel, Jean Paul; White, Charles L; Wisniewski, Thomas; Woltjer, Randall L; Yamada, Masahito; Nelson, Peter T

    2014-12-01

    We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

  5. Vibration transmission through sheet webs of hobo spiders (Eratigena agrestis) and tangle webs of western black widow spiders (Latrodectus hesperus).

    Science.gov (United States)

    Vibert, Samantha; Scott, Catherine; Gries, Gerhard

    2016-11-01

    Web-building spiders construct their own vibratory signaling environments. Web architecture should affect signal design, and vice versa, such that vibratory signals are transmitted with a minimum of attenuation and degradation. However, the web is the medium through which a spider senses both vibratory signals from courting males and cues produced by captured prey. Moreover, webs function not only in vibration transmission, but also in defense from predators and the elements. These multiple functions may impose conflicting selection pressures on web design. We investigated vibration transmission efficiency and accuracy through two web types with contrasting architectures: sheet webs of Eratigena agrestis (Agelenidae) and tangle webs of Latrodectus hesperus (Theridiidae). We measured vibration transmission efficiencies by playing frequency sweeps through webs with a piezoelectric vibrator and a loudspeaker, recording the resulting web vibrations at several locations on each web using a laser Doppler vibrometer. Transmission efficiencies through both web types were highly variable, with within-web variation greater than among-web variation. There was little difference in transmission efficiencies of longitudinal and transverse vibrations. The inconsistent transmission of specific frequencies through webs suggests that parameters other than frequency are most important in allowing these spiders to distinguish between vibrations of prey and courting males.

  6. Effect of Sea Tangle ( and Charcoal Supplementation as Alternatives to Antibiotics on Growth Performance and Meat Quality of Ducks

    Directory of Open Access Journals (Sweden)

    M. M. Islam

    2014-02-01

    Full Text Available A total of 150 growing ducks were assigned to five dietary treatments to study the effect of sea tangle and charcoal (STC supplementation on growth performance and meat characteristics in a completely randomized design. There were six replicates and five ducklings in each replication. The five dietary treatments were control, antibiotic, and 0.1%, 0.5%, and 1% STC supplemented diets. No significant differences were found on ADG, ADFI, and gain:feed among treatments in different weeks. The overall (0 to 3 weeks ADFI decreased in antibiotic treatment (p<0.05 whereas the gain:feed increased significantly upon 1.0% STC supplementation compared to control (p<0.05. No significant variation was found in meat chemical composition except crude fat content which was high in 1.0% STC dietary group (p<0.05. Meat cholesterol was reduced in 0.1% STC group (p<0.05 compared to other dose levels while serum cholesterol was unaffected. High density lipoprotein (HDL content was high in 1.0% STC (p<0.05 and low density lipoprotein (LDL was low in 0.1% and 1.0% STC dietary groups (p = 0.06. No significant effect was found on the thiobarbituric acid reactive substances (TBARS of fresh meat, whereas the TBARS value of meat preserved for 1 week was reduced significantly in STC dietary groups (p<0.05. The 0.1% STC dietary group showed an increased myristic acid (p = 0.07 content whereas, the content of eicosapentaenoic (EPA and docosahexaenoic (DHA acids increased in STC supplementation than antibiotic group (p<0.05. An increased concentration of omega-3 fatty acids and a reduced ratio of n-6/n-3 PUFA ratio was found upon 1.0% STC supplementation compared to antibiotic dietary group (p<0.05. Therefore, 1.0% STC dietary supplementation can be used as alternatives to antibiotics in duck production.

  7. Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe.

    Science.gov (United States)

    Verwilst, Peter; Kim, Hye-Ri; Seo, Jinho; Sohn, Nak-Won; Cha, Seung-Yun; Kim, Yeongmin; Maeng, Sungho; Shin, Jung-Won; Kwak, Jong Hwan; Kang, Chulhun; Kim, Jong Seung

    2017-09-27

    The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 (306VQIVYK311) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

  8. Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles.

    Science.gov (United States)

    Di Meco, Antonio; Joshi, Yash B; Praticò, Domenico

    2014-08-01

    Several studies have highlighted the frequency of sleep disturbances in Alzheimer's disease (AD). However, whether they are secondary to the disease or per se increase its risk remains to be fully investigated. The aim of the current investigation was to study the effect of sleep deprivation (SD) on the development of AD phenotype in a transgenic mouse model with plaques and tangles, the 3xTg mice. We evaluated the functional and biological consequences on 3xTg mice that underwent 4 hours sleep restrain per day for 8 weeks. Compared with controls, behavioral assessment showed that SD-treated mice had a significant decline in their learning and memory. Although no differences were detected in the levels of soluble amyloid-β peptides, the same animals displayed a decrease in tau phosphorylation, which associated with a significant increase in its insoluble fraction. In addition, we observed that SD resulted in lower levels of postsynaptic density protein 95 and increased glial fibrillary acidic protein levels. Finally, although total levels of the transcription factor cellular response element binding protein were unchanged, its phosphorylated form was significantly diminished in brains of sleep-deprived mice when compared with controls. Our study underlines the importance of SD as a chronic stressor, which by modulating biochemical processes influences the development of memory impairments and AD neuropathologies. Correction of SD could be a viable therapeutic strategy to prevent the onset or slow the progression of AD in individuals bearing this risk factor. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Crescimento e produtividade do tomateiro em cultivo hidropônico NFT em função da concentração iônica da solução nutritiva Growing and yield of tomato in hydroponic cultivation as a result of the ionic concentration of the nutritive solution

    Directory of Open Access Journals (Sweden)

    Gláucio da C Genúncio

    2006-06-01

    Full Text Available O cultivo hidropônico do tomateiro é uma técnica com a qual pode-se obter maior produtividade e melhoria no controle de diversos fatores durante o ciclo produtivo. Entretanto, essa técnica ainda requer aprimoramento em vários aspectos, dentre eles, as doses de nutrientes na solução nutritiva. Neste sentido, um experimento foi conduzido em casa de vegetação equipada com sistema hidropônico tipo fluxo contínuo de nutrientes (nutrient film technique; NFT. Foram utilizadas as cultivares de tomate UC-82, Saladinha e T-93 supridas com solução nutritiva de Hoagland nas concentrações iônicas 50%; 75% e 100%. Na última coleta de frutos, aos 138 dias após a transferência para o sistema NFT, colheram-se as plantas e avaliaram-se o acúmulo de massa na parte aérea, massa fresca de fruto, número de frutos por planta, massa fresca total de frutos por planta, teor de sólidos solúveis totais (ºBrix e produtividade. As características genotípicas das cultivares influenciaram fortemente a produtividade. De modo geral, as diferentes concentrações iônicas das soluções nutritivas, nas condições em que foi desenvolvido o trabalho, não influenciaram a produtividade e o acúmulo de massa dos tomateiros. Portanto é recomendável o uso de soluções de menor concentração iônica para o cultivo de tomateiros UC-82, Saladinha e T-93 em sistema hidropônico NFT, nas condições climáticas de Seropédica, Rio de Janeiro.The tomato hydroponics cultivation is a technique that provides high productivity and a better control of several factors during the production cycle. However, this technique needs improvements such as adequate dosage of nutrients in the nutritive solution. An experiment was carried out in a greenhouse equipped with a nutrient film technique system (NFT. Three commercial cvs. of tomato, UC-82, Saladinha, and T-93, were grown with three Hoagland's solution concentrations, 50%; 75%; and 100%. In the last fruit harvest, 138

  10. Chronic noise exposure and Alzheimer disease: Is there an etiological association?

    Science.gov (United States)

    Cui, Bo; Li, Kang

    2013-10-01

    Recent work has implicated environmental stimuli as contributing to the risk of developing Alzheimer's disease (AD). Noise is one of the most important environmental health hazards for humans. Here, we propose that noise exposure, especially chronic noise exposure, can cause AD-like neuropathological changes, and that persistence of these changes have an etiological association with the development of AD. Noise can induce tau hyperphosphorylation, formation of neurofibrillary tangles (NFT) and increase β-amyloid (Aβ) and amyloid precursor protein (APP) and thus could be pivotal to AD pathogenesis and progression. The aberrant accumulation of NFT and Aβ could promote synaptic malfunction and apoptosis of neurons, which eventually could lead to Alzheimer dementia. Noise-induced excitotoxicity and oxidative stress are associated with AD-like neuropathology and an increasing risk for the development of AD. Noise can induce excitotoxicity and oxidative stress which might be one of the mechanisms how noise exposure could increase AD risk. To test this hypothesis, epidemiological studies should be carried out. On the other hand, in addition to its potential risk for the development of AD, noise exposure has many other harmful effects which warrant that actions should be taken to protect the public health from noise hazards without waiting for the results of these studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Spatial Analysis of the Neuronal Density of Aminergic Brainstem Nuclei in Primary Neurodegenerative and Vascular Dementia: A Comparative Immunocytochemical and Quantitative Study Using a Graph Method

    Directory of Open Access Journals (Sweden)

    Yan Yang

    1999-01-01

    Full Text Available A graph method was employed to analyse spatial neuronal patterns of pontine nuclei with ascending aminergic projections to the forebrain (nucleus centralis superior (NCS, raphes dorsalis (NRD and locus coeruleus (LC, in Alzheimer disease (AD, Huntington disease (HD, and vascular (VD as well as “mixed‐type” (VA dementia, compared with non‐demented controls (CO and a small sample of brains from schizophrenics (“dementia praecox” (DP. The quantitative evaluations by the “minimal spanning tree (MST” were complemented by rough neurofibrillary tangle (NFT counts and by semiquantitative immunohistochemical assessment of amyloid deposition, neuritic plaque formation, and cellular gliosis. The AD cases showed a significant decline of neuronal density in all nuclei examined, as compared with controls and DP. Neuronal loss was not significant in VD, while the mixed cases with both vascular and Alzheimer‐type pathology exhibited pronounced changes of neuronal density. Amyloid deposition occurred almost exclusively in AD and VA, as a rule, being of moderate degree, except for two presenile AD cases where it was marked. NFT were significantly increased in all nuclei in AD and in the VA cases, while they only occasionally appeared beyond age 55 in HD, DP and CO. The four HD cases showed in the NCS and NRD neuronal loss as severe as in AD. This neuronal loss implicates impairment of serotoninergic and noradrenergic neuromodulation as one basic mechanism promoting dementia in AD, VA and perhaps in HD.

  12. Factors Determining Disease Duration in Alzheimer’s Disease: A Postmortem Study of 103 Cases Using the Kaplan-Meier Estimator and Cox Regression

    Directory of Open Access Journals (Sweden)

    R. A. Armstrong

    2014-01-01

    Full Text Available Factors associated with duration of dementia in a consecutive series of 103 Alzheimer’s disease (AD cases were studied using the Kaplan-Meier estimator and Cox regression analysis (proportional hazard model. Mean disease duration was 7.1 years (range: 6 weeks–30 years, standard deviation = 5.18; 25% of cases died within four years, 50% within 6.9 years, and 75% within 10 years. Familial AD cases (FAD had a longer duration than sporadic cases (SAD, especially cases linked to presenilin (PSEN genes. No significant differences in duration were associated with age, sex, or apolipoprotein E (Apo E genotype. Duration was reduced in cases with arterial hypertension. Cox regression analysis suggested longer duration was associated with an earlier disease onset and increased senile plaque (SP and neurofibrillary tangle (NFT pathology in the orbital gyrus (OrG, CA1 sector of the hippocampus, and nucleus basalis of Meynert (NBM. The data suggest shorter disease duration in SAD and in cases with hypertensive comorbidity. In addition, degree of neuropathology did not influence survival, but spread of SP/NFT pathology into the frontal lobe, hippocampus, and basal forebrain was associated with longer disease duration.

  13. Thal Amyloid Stages Do Not Significantly Impact the Correlation Between Neuropathological Change and Cognition in the Alzheimer Disease Continuum.

    Science.gov (United States)

    Serrano-Pozo, Alberto; Qian, Jing; Muzikansky, Alona; Monsell, Sarah E; Montine, Thomas J; Frosch, Matthew P; Betensky, Rebecca A; Hyman, Bradley T

    2016-06-01

    The 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer's Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  14. Tangling with telecomes

    CSIR Research Space (South Africa)

    Roux, S

    2011-07-01

    Full Text Available At the CSIR’s National Laser Centre, a team of researchers is pursuing Free Space Quantum Communication: transmitting optical signals by using the quantum properties of laser light. The aim is to provide secure and safe ways of communication using...

  15. Tangled up in black - a study of the activist strategies of the Black Power movement through the life of Gary Foley

    OpenAIRE

    Howell, Edwina Maurey

    2017-01-01

    Tangled Up in Black is a work of anthropology that both critiques and celebrates the discipline as much as it does the subject of the thesis, ‘A study of the activist strategies of the Black Power movement (in Australia) through the life of Gary Foley’. It is most influenced by the life work of the subject, Gary Foley as well as that of anthropologist Michael Taussig and philosopher and literary critic, Walter Benjamin, in particular his ‘Thesis on the Philosophy of History’. I have enga...

  16. Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model

    Science.gov (United States)

    Cook, Casey; Kang, Silvia S.; Carlomagno, Yari; Lin, Wen-Lang; Yue, Mei; Kurti, Aishe; Shinohara, Mitsuru; Jansen-West, Karen; Perkerson, Emilie; Castanedes-Casey, Monica; Rousseau, Linda; Phillips, Virginia; Bu, Guojun; Dickson, Dennis W.; Petrucelli, Leonard; Fryer, John D.

    2015-01-01

    Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-TauP301L mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets. PMID:26276810

  17. Vascular Contributions in Alzheimer's Disease-Related Neuropathological Changes: First Autopsy Evidence from a South Asian Aging Population.

    Science.gov (United States)

    Wijesinghe, Printha; Shankar, S K; Yasha, T C; Gorrie, Catherine; Amaratunga, Dhammika; Hulathduwa, Sanjayah; Kumara, K Sunil; Samarasinghe, Kamani; Suh, Yoo-Hun; Steinbusch, Harry W M; De Silva, K Ranil D

    2016-10-18

    Evidence from various consortia on vascular contributions has been inconsistent in determining the etiology of sporadic Alzheimer's disease (AD). To investigate vascular risk factors and cerebrovascular pathologies associated in manifestation of AD-related neuropathological changes of an elderly population. Postmortem brain samples from 76 elderly subjects (≥50 years) were used to study genetic polymorphisms, intracranial atherosclerosis of the circle of Willis (IASCW), and microscopic infarcts in deep white matters. From this cohort, 50 brains (≥60 years) were subjected to neuropathological diagnosis using immunohistopathological techniques. Besides the association with age, the apolipoprotein E ɛ4 allele was significantly and strongly associated with Thal amyloid-β phases ≥1 [odds ratio (OR) = 6.76, 95% confidence interval (CI) 1.37-33.45] and inversely with Braak neurofibrillary tangle (NFT) stages ≥III (0.02, 0.0-0.47). Illiterates showed a significant positive association for Braak NFT stages ≥IV (14.62, 1.21-176.73) and a significant negative association for microscopic infarcts (0.15, 0.03-0.71) in deep white matters. With respect to cerebrovascular pathologies, cerebral small vessel lesions (white matter hyperintensities and cerebral amyloid angiopathy) showed a higher degree of associations among them and with AD-related neuropathological changes (p pathology (IASCW), which showed a significant association only with Braak NFT stages ≥I (p = 0.050). These findings suggest that besides age, education, and genetic factors, other vascular risk factors were not associated with AD-related neuropathological changes and urge prompt actions be taken against cerebral small vessel diseases since evidence for effective prevention is still lacking.

  18. Phosphorylation of tau protein at sites Ser(396-404) is one of the earliest events in Alzheimer's disease and Down syndrome.

    Science.gov (United States)

    Mondragón-Rodríguez, S; Perry, G; Luna-Muñoz, J; Acevedo-Aquino, M C; Williams, S

    2014-02-01

    Phosphorylation, conformational changes and cleavage of tau protein have been widely suggested to contribute to abnormal tau processing in the pathogenesis of Alzheimer's disease, as well as in other tauopathies. Consistently, many phosphorylated sites, such as Ser(199-202) -Thr(205) and Ser(396-404) , have been associated with this pathological processing. The present study examined the chronological appearance of phosphorylation during the neurofibrillary tangle (NFT) evolution in Alzheimer disease (AD) and Down syndrome. Immunohistochemistry for modified tau [phosphorylated at Ser(199-202) -Thr(205) (AT8) and Ser(396-404) (PHF-1) or truncated at D(421) (TauC3) and E(391) (MN423)] was performed on paraffin-embedded human brain sections. Double immunofluorescence for phosphorylated and truncated tau was used to detect intensity and distribution of tau immunoreactivity, and provided detailed characterization of NFT pathology. Phosphorylation at sites Ser(396-404) was significantly increased when compared with phosphorylations at sites Ser(199-202) -Thr(205) . Around 50% of the total structures containing phosphorylation at sites Ser(396-404) were found as early phospho-tau aggregates with a well-preserved neuronal soma. Phosphorylation of tau protein at sites Ser(396) coexists with early and late truncation events. Tau abnormal processing in Down syndrome consistently showed similar alterations as observed in AD. Phosphorylation of tau protein at the carboxyl terminus may be among the earliest tau events, and it occurs prior to the apparition of the classical fibrillar structure. Finally, these data validate PHF-1 as an efficient marker for AD cytopathology following the progression of tau aggregation into NFT. © 2013 British Neuropathological Society.

  19. Creating a Simian Model of Guam ALS/PDC Which Reflects Chamorro Lifetime BMAA Exposures.

    Science.gov (United States)

    Banack, Sandra Anne; Cox, Paul Alan

    2018-01-01

    The theory that β-N-methylamino-L-alanine (BMAA), a cyanobacterial toxin, contaminates traditional food supplies of the Chamorro people of Guam is supported by the recent finding that chronic dietary exposure to L-BMAA in vervets (Chlorocebus sabaeus) triggers the formation of neurofibrillary tangles (NFT) and β-amyloid plaques in the brain. In the first experiment, we found that all four vervets receiving a 210 mg/kg dose for 140 days developed NFT and sparse amyloid deposits. In the second experiment, all eight vervets receiving a 210 mg/kg dose for 140 days developed NFT and amyloid deposits, as well as all eight vervets that received only 21 mg/kg. Based on dietary surveys of the Chamorro people, we estimated lifetime chronic BMAA exposure at a high and a low level: 1) adult male Chamorros eating two flying foxes per month plus one 30 g serving of cycad flour per week; and 2) adult male Chamorros eating one 30 g serving of cycad flour per day combined with the consumption of eight flying foxes per month. The resultant cumulative lifetime Chamorro exposures ranged from 1 to 41 g/kg and are comparable to the total lifetime vervet exposures in our experiments of 2 and 22 g/kg, respectively. Furthermore, measured protein-bound BMAA concentrations of vervets fed L-BMAA powder are comparable to measured protein-bound BMAA concentrations in postmortem brain tissues of Chamorros who died with ALS/PDC.

  20. Early-onset axonal pathology in a novel P301S-Tau transgenic mouse model of frontotemporal lobar degeneration.

    Science.gov (United States)

    van Eersel, Janet; Stevens, Claire H; Przybyla, Magdalena; Gladbach, Amadeus; Stefanoska, Kristie; Chan, Chesed Kai-Xin; Ong, Wei-Yi; Hodges, John R; Sutherland, Greg T; Kril, Jillian J; Abramowski, Dorothee; Staufenbiel, Matthias; Halliday, Glenda M; Ittner, Lars M

    2015-12-01

    Tau becomes hyperphosphorylated in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD-tau), resulting in functional deficits of neurones, neurofibrillary tangle (NFT) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD-tau and AD. In this study, we characterized the novel P301S mutant tau transgenic mouse line, TAU58/2. Both young and aged TAU58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. TAU58/2 mice presented with early-onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament (NF) were present in young TAU58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD-tau and AD. Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF-positive axonal swellings. In TAU58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD-tau, but not in FTLD with TDP-43 inclusions. Therefore, TAU58/2 mice recapitulate aspects of human FTLD-tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future. © 2015 British Neuropathological Society.

  1. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy.

    Science.gov (United States)

    Armstrong, Richard A; McKee, Ann C; Alvarez, Victor E; Cairns, Nigel J

    2017-02-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE. In CTE: (1) all aspects of tau-immunoreactive pathology were clustered and the clusters were frequently regularly distributed parallel to the tissue boundary, (2) clustering was similar in two CTE cases with minimal co-pathology compared with cases with associated ADNC or TDP-43 proteinopathy, (3) in a proportion of cortical gyri, estimated cluster size was similar to that of cell columns of the cortico-cortical pathways, and (4) clusters of the tau-immunoreactive pathology were infrequently spatially correlated with blood vessels. The NFT and NP in ADNC without CTE were less frequently randomly or uniformly distributed and more frequently in defined clusters than in CTE. Hence, the spatial pattern of the tau-immunoreactive pathology observed in CTE is typical of the tauopathies but with some distinct differences compared to ADNC alone. The spread of pathogenic tau along anatomical pathways could be a factor in the pathogenesis of the disease.

  2. [Suspected Non-Alzheimer's Disease Pathophysiology (SNAP) and Its Pathological Backgrounds in the Diagnosis of Preclinical and Clinical Alzheimer's Disease].

    Science.gov (United States)

    Yamada, Masahito

    2018-01-01

    Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker-based condition that is found in individuals with normal levels of amyloid-β protein (Aβ) markers (A-) and abnormal levels of markers of neurodegeneration or neuronal injury (N+). SNAP is found in 20-26% of cognitively normal (CN) individuals aged 65 years or older and 17-35% of individuals with mild cognitive impairment (MCI). Similarly, 7-39% of patients with clinically probable Alzheimer's disease (AD) dementia are negative for Aβ. The ε4 allele of the apolipoprotein E gene is underrepresented in individuals with SNAP compared with amyloid-positive (A+) groups. The progression of the cognitive impairments of individuals with SNAP was slower than that of A+N+ subjects who had a high likelihood of AD pathophysiology and faster than that of A-N- subjects. The pathological backgrounds of the individuals with SNAP were heterogeneous and included cerebrovascular disorders, mixed pathologies, and non-AD neurodegeneration, such as primary age-related tauopathy [PART, also known as senile dementia of the neurofibrillary tangle type (SD-NFT) (tangle-only dementia) at the dementia stage] and argyrophilic grain disease. Further clarification of SNAP is needed to better define the mechanisms underlying the progression of AD pathologies in older individuals.

  3. The Tangled Branches (Las Ramas Enredadas): Sexual Risk, Substance Abuse, and Intimate Partner Violence Among Hispanic Men who Have Sex with Men

    Science.gov (United States)

    De Santis, Joseph P.; Gonzalez-Guarda, Rosa; Provencio-Vasquez, Elias; Deleon, Diego A.

    2012-01-01

    Hispanic men who have sex with men (MSM) experience a number of health disparities including high rates of HIV infection from high risk sex, substance abuse, and intimate partner violence. Although some research is available to document the relationships of these health disparities in the literature, few studies have explored the intersection of these disparities and the factors that influence them. The purpose of this study was to explore the experiences that Hispanic MSM residing in South Florida have with high risk sex, substance abuse, and intimate partner violence. Focus groups were conducted and analyzed using grounded theory methodology until data saturation was reached (n = 20). Two core categories with subcategories emerged from the data: The Roots of Risk (Los raices del riesgo) and The Tangled Branches (Las Ramas Enredadas). The results of the study provided some important clinical implications as well as directions for future research with Hispanic MSM. PMID:24084703

  4. The Tangled Branches (Las Ramas Enredadas): sexual risk, substance abuse, and intimate partner violence among Hispanic men who have sex with men.

    Science.gov (United States)

    De Santis, Joseph P; Gonzalez-Guarda, Rosa; Provencio-Vasquez, Elias; Deleon, Diego A

    2014-01-01

    Hispanic men who have sex with men (MSM) experience a number of health disparities including high rates of HIV infection from high-risk sex, substance abuse, and intimate partner violence. Although some research is available to document the relationships of these health disparities in the literature, few studies have explored the intersection of these disparities and the factors that influence them. The purpose of this study was to explore the experiences that Hispanic MSM residing in South Florida have with high-risk sex, substance abuse, and intimate partner violence. Focus groups were conducted and analyzed using grounded theory methodology until data saturation was reached (n = 20). Two core categories with subcategories emerged from the data: The Roots of Risk (Los raices del riesgo) and The Tangled Branches (Las Ramas Enredadas). The results of the study provided some important clinical implications as well as directions for future research with Hispanic MSM.

  5. Brain Aging in the Oldest-Old

    Directory of Open Access Journals (Sweden)

    A. von Gunten

    2010-01-01

    Full Text Available Nonagenarians and centenarians represent a quickly growing age group worldwide. In parallel, the prevalence of dementia increases substantially, but how to define dementia in this oldest-old age segment remains unclear. Although the idea that the risk of Alzheimer's disease (AD decreases after age 90 has now been questioned, the oldest-old still represent a population relatively resistant to degenerative brain processes. Brain aging is characterised by the formation of neurofibrillary tangles (NFTs and senile plaques (SPs as well as neuronal and synaptic loss in both cognitively intact individuals and patients with AD. In nondemented cases NFTs are usually restricted to the hippocampal formation, whereas the progressive involvement of the association areas in the temporal neocortex parallels the development of overt clinical signs of dementia. In contrast, there is little correlation between the quantitative distribution of SP and AD severity. The pattern of lesion distribution and neuronal loss changes in extreme aging relative to the younger-old. In contrast to younger cases where dementia is mainly related to severe NFT formation within adjacent components of the medial and inferior aspects of the temporal cortex, oldest-old individuals display a preferential involvement of the anterior part of the CA1 field of the hippocampus whereas the inferior temporal and frontal association areas are relatively spared. This pattern suggests that both the extent of NFT development in the hippocampus as well as a displacement of subregional NFT distribution within the Cornu ammonis (CA fields may be key determinants of dementia in the very old. Cortical association areas are relatively preserved. The progression of NFT formation across increasing cognitive impairment was significantly slower in nonagenarians and centenarians compared to younger cases in the CA1 field and entorhinal cortex. The total amount of amyloid and the neuronal loss in these regions

  6. Insulin dysfunction and Tau pathology

    Directory of Open Access Journals (Sweden)

    Noura eEl Khoury

    2014-02-01

    Full Text Available The neuropathological hallmarks of Alzheimer's disease (AD include senile plaques of β-amyloid (Aβ peptides (a cleavage product of the Amyloid Precursor Protein, or APP and neurofibrillary tangles (NFT of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF. NFT pathology is important since it correlates with the degree of cognitive impairment in AD.Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99% is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease.Insulin dysfunction, manifested by diabetes mellitus (DM might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM and type 2 diabetes (T2DM are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment.Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting on Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

  7. Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

    Science.gov (United States)

    Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

    2011-01-01

    Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. PMID:21416485

  8. Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia.

    Science.gov (United States)

    Fujishiro, Hiroshige; Iseki, Eizo; Higashi, Shinji; Kasanuki, Koji; Murayama, Norio; Togo, Takashi; Katsuse, Omi; Uchikado, Hirotake; Aoki, Naoya; Kosaka, Kenji; Arai, Heii; Sato, Kiyoshi

    2010-12-03

    Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  9. Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla).

    Science.gov (United States)

    Perez, Sylvia E; Raghanti, Mary Ann; Hof, Patrick R; Kramer, Lynn; Ikonomovic, Milos D; Lacor, Pascale N; Erwin, Joseph M; Sherwood, Chet C; Mufson, Elliott J

    2013-12-15

    The two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD-related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau-like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age-related increase in Aβ-immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ-positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40-, Aβ42-, and Aβ oligomer-immunoreactive, but only weakly thioflavine S- or 6-CN-PiB-positive in both sexes, indicative of the less fibrillar (diffuse) nature of Aβ plaques in gorillas. Although phosphorylated neurofilament immunostaining revealed a few dystrophic neurites and neurons, choline acetyltransferase-immunoreactive fibers were not dystrophic. Neurons stained for the tau marker Alz50 were found in the neocortex and hippocampus of gorillas at all ages. Occasional Alz50-, MC1-, and AT8-immunoreactive astrocyte and oligodendrocyte coiled bodies and neuritic clusters were seen in the neocortex and hippocampus of the oldest gorillas. This study demonstrates the spontaneous presence of both Aβ plaques and tau-like lesions in the neocortex and hippocampus in old male and female western lowland gorillas, placing this species at relevance in the context of AD research. Copyright © 2013 Wiley Periodicals, Inc.

  10. Dementia and diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Pavlović Dragan M.

    2008-01-01

    Full Text Available Dementia and Diabetes mellitus (DM are major health problems nowadays. DM leads to a significant cognitive decline and increases the risk of dementia, mostly Alzheimer's Disease (AD and vascular dementia (VaD by 50-100% and 100-150%, respectively. Amyloid beta (Abeta, the main pathogenic factor in AD development, is eliminated by advanced glycation end products (AGEs and degraded by insulin degrading enzyme (IDE for which it competes with insulin. Insulin stimulates secretion of Abeta and promotes brain inflammation. DM I and II cause slowing down of mental speed, lowering of mental flexibility and DM II learning and memory disturbances. DM acts both directly by hyperglycaemia and hyperinsulinaemia and by the blood vessel changes. Hyperglycaemia changes synapse plasticity and leads to cognitive decline. AGEs disrupt the neuron function and bonding to Abeta increases its aggregability. Glycation of tau protein promotes production of neurofibrillary tangles (NFT, the main intracellular pathogenic factor in AD. AGE2 in DM causes pathological angiogenesis and apoptosis of neurons. AGE receptor (RAGE is also the specific Abeta receptor with which it produces reactive oxygen species that has, as a result, disruption of mitochondrial function and reduction of neuronal energy resources. Insulinoresistance is linked with the dysexecutive syndrome, and hyperinsulinaemia increases the risk of AD especially by enhancing phosphorylation of tau protein and formation of NFT. Application of insulin showed improvement of memory, behaviour and affect in AD patients. Good glycoregulation emerged as an important factor in dementia prevention, and a better insight in relations of DM and brain function will lead to new potential dementia therapies. .

  11. Relationship between genetic risk factors and markers for Alzheimer's disease pathology

    NARCIS (Netherlands)

    Elias-Sonnenschein, L.S.; Bertram, L.; Visser, P.J.

    2012-01-01

    Alzheimers disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: -amyloid [A]) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. Abnormalities in A and tau can be measured upon neuropathological examination, in cerebrospinal fluid

  12. Medline Plus

    Full Text Available In a person with Alzheimer disease, neurofibrillary tangles and plaques develop causing both structural and chemical problems in the brain. Alzheimer disease appears to disconnect areas ...

  13. Medline Plus

    Full Text Available In a person with Alzheimer disease, neurofibrillary tangles and plaques develop causing both structural and chemical problems in the brain. Alzheimer disease appears to disconnect areas of ...

  14. "A Complicated Tangle of Circumstances"

    Science.gov (United States)

    Miller, Carole; Saxton, Juliana

    2009-01-01

    The post-modern curriculum, drawing on chaos and complexity theory, recognises the realities of a world in flux and posits that the teacher and the class are always teetering "in the midst" of chaos, "not linked by chains of causality but [by] layers of meaning, recursive dynamics, non-linear effects and chance" (Osberg 2008,…

  15. The Tangle of Student Allowances.

    Science.gov (United States)

    Thomson, Norman J.

    1980-01-01

    A discussion of the distribution of student financial aid in Australia focuses on these issues: direct vs. indirect payment to students; inequality in living allowances given to secondary and postsecondary students; and distribution of expense allowances by state government and living allowances by the Commonwealth. (MSE)

  16. Hematopoietic Stem Cell and Its Growth Factor

    Science.gov (United States)

    1988-02-16

    senile dementia of the Alzheimer type share an antigenic deermi oclonsi antibody specific for Lactasyiceramide. J. fBo. Chem. nant with intermediate...erythroblast. Blood 63:1376, 1984. 10. Yen SH, Gaskin F, Fu SM: Neurofibrillary tangles in senile dementia of the Alzheimer type share an antigenic...and induced globin expression. Science 216:1233. 59 21. Yen SH, F Gaskin and SM Fu. 1983. Neurofibrillary tangles in senile dementia of the Alzheimer

  17. Tangent map intermittency as an approximate analysis of intermittency in a high dimensional fully stochastic dynamical system: The Tangled Nature model

    Science.gov (United States)

    Diaz-Ruelas, Alvaro; Jeldtoft Jensen, Henrik; Piovani, Duccio; Robledo, Alberto

    2016-12-01

    It is well known that low-dimensional nonlinear deterministic maps close to a tangent bifurcation exhibit intermittency and this circumstance has been exploited, e.g., by Procaccia and Schuster [Phys. Rev. A 28, 1210 (1983)], to develop a general theory of 1/f spectra. This suggests it is interesting to study the extent to which the behavior of a high-dimensional stochastic system can be described by such tangent maps. The Tangled Nature (TaNa) Model of evolutionary ecology is an ideal candidate for such a study, a significant model as it is capable of reproducing a broad range of the phenomenology of macroevolution and ecosystems. The TaNa model exhibits strong intermittency reminiscent of punctuated equilibrium and, like the fossil record of mass extinction, the intermittency in the model is found to be non-stationary, a feature typical of many complex systems. We derive a mean-field version for the evolution of the likelihood function controlling the reproduction of species and find a local map close to tangency. This mean-field map, by our own local approximation, is able to describe qualitatively only one episode of the intermittent dynamics of the full TaNa model. To complement this result, we construct a complete nonlinear dynamical system model consisting of successive tangent bifurcations that generates time evolution patterns resembling those of the full TaNa model in macroscopic scales. The switch from one tangent bifurcation to the next in the sequences produced in this model is stochastic in nature, based on criteria obtained from the local mean-field approximation, and capable of imitating the changing set of types of species and total population in the TaNa model. The model combines full deterministic dynamics with instantaneous parameter random jumps at stochastically drawn times. In spite of the limitations of our approach, which entails a drastic collapse of degrees of freedom, the description of a high-dimensional model system in terms of a low

  18. Hydroponic lettuce production in different concentrations and flow rates of nutrient solution Produção de cultivares de alface em sistema NFT variando concentração e vazão da solução

    Directory of Open Access Journals (Sweden)

    Gláucio da C Genuncio

    2012-09-01

    Full Text Available The objective of this study was to evaluate the accumulation of fresh weight of hydroponic lettuce in terms of ionic concentrations and flow rates of nutrient solution. This work consisted of three experiments in NFT hydroponic system, conducted between July and September 2006. Lettuce cultivars Lucy Brown, Izabela and Veneza were grown in different ionic concentrations of the 100, 75 and 50% and flow rates of 1.50, 1.00 and 0.75 L min-1. Fresh weight gains were observed for Lucy Brown when grown on 100% of the ion concentration and a flow rate of nutrient solution of 1.0 L min-1. Greater fresh mass was observed for cvs. Izabela and Veneza under the flow rate of 1.5 L min-1. A general analysis of the data allows us to conclude that the application of nutrient solution at a flow rate of 1.5 L min-1, as well as 100% of the ionic concentration is effective to increase the fresh weight of the aerial part of cvs. Lucy Brown, Izabela and Veneza when grown in hydroponics.O objetivo deste trabalho foi avaliar o acúmulo de massa fresca em cultivares de alface hidropônica em função de concentrações iônicas e de vazões de solução nutritiva. O trabalho consistiu em três experimentos em sistema hidropônico NFT, conduzidos entre julho e setembro de 2006. Cultivares de alface Lucy Brown, Izabela e Veneza foram crescidas em concentrações iônicas de 100, 75 e 50% e vazões de 1,50; 1,00 e 0,75 L min-1. Ganhos de massa fresca foram observados para Lucy Brown quando cultivada a 100% da concentração iônica e a uma vazão de solução nutritiva acima de 1,0 L min-1. Para Izabela e Veneza maiores massas frescas foram observadas em vazão de 1,5 L min-1 e 100% de concentração iônica. Uma análise geral dos dados nos permite concluir que a aplicação da solução nutritiva a uma vazão de 1,5 L min-1, assim como 100% da concentração iônica é eficiente para acréscimos de massa fresca de parte aérea para cultivares Lucy Brown, Izabela e Veneza

  19. Application of PIXE in medical study. Environmental minerals and neurodegenerative disorders

    Energy Technology Data Exchange (ETDEWEB)

    Yoshida, S. [Department of Neurology, Wakayama Medical College, Wakayama (Japan)

    1999-07-01

    Comparative study on amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PDC) in the Kii Peninsula of Japan and Guam was conducted to evaluate the participatory role of environmental minerals in the pathogenesis of the above neurodegenerative diseases, using particle-induced x-ray emission (PIXE) spectrometry and morphometric-statistical analysis. A significantly high content of Al in the hippocampus and spinal cord or Kii and Guamanian ALS/PD cases was found with a positive correlation for Fe and Cu, and a negative correlation for Zn. The numbers of hippocampal neurons in Guamanian PDC, Alzheimer's disease, and Parkinson's disease were significantly decreased with a high Al content. Al content significantly and positively correlated with the number of Alzheimer's neurofibrillary tangles (NFTs) in the hippocampus of ALS cases and controls in both foci, especially in Guamanian cases. The slope of best linear regression of Guamanian cases was markedly steeper than that of Japanese cases (p < 0,001), Morin staining for Al showed green fluorescence on the nucleolus, cytoplasm, and NFT in the hippocampus of Kii ALS cases. These findings suggest that Guamanian and Kii people have a predisposition to develop ALS/PDC precipitated by their geological/geochemical environmental status, i.e., a prolonged low intake or Ca and Mg together with excess exposure to Al and other environmental minerals. (author)

  20. Multifaceted effects of aluminium in neurodegenerative diseases: A review.

    Science.gov (United States)

    Maya, S; Prakash, T; Madhu, Krishna Das; Goli, Divakar

    2016-10-01

    Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well-established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. Combined administration of D-galactose and aluminium induces Alzheimer-like lesions in brain.

    Science.gov (United States)

    Xiao, Fei; Li, Xiao-Guang; Zhang, Xiao-Yu; Hou, Jun-Dai; Lin, Lian-Feng; Gao, Qin; Luo, Huan-Min

    2011-06-01

    It has been reported that D-galactose (D-gal) can model subacute aging, and aluminum (Al) acts as a neurotoxin, but combined effects of them have not been reported. The present work aimed to reveal the effect of combined administration of D-gal and Al in mice and compare the effect of D-gal treatment with that of Al treatment. Al was intragastrically administered and D-gal was subcutaneously injected into Kunming mice for 10 consecutive weeks. Learning and memory, cholinergic systems, as well as protein levels of amyloid β (Aβ) and hyperphosphorylated tau were determined using Morri water maze test, biochemical assays and immunohistochemical staining, respectively. The mice with combined treatment had obvious learning and memory deficits, and showed decreases in brain acetylcholine (ACh) level and in activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE). Formation of senile plaque (SP)-like and neurofibrillary tangle (NFT)-like structures was also observed. The behavioral and pathological changes persisted for at least 6 weeks after withdrawal of D-gal and Al. Combined use of D-gal and Al is an effective way to establish the non-transgenic Alzheimer's disease (AD) animal model, and is useful for studies of AD pathogenesis and therapeutic evaluation.

  2. The Implication of the Brain Insulin Receptor in Late Onset Alzheimer’s Disease Dementia

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    Jaume Folch

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ, which form senile plaques, neurofibrillary tangles (NFT and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the “peripheral” symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors.

  3. An Autopsy Proven Child Onset Chronic Traumatic Encephalopathy.

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    Lee, Kyuho; Kim, Seong-Ik; Lee, Yujin; Won, Jae Kyung; Park, Sung-Hye

    2017-06-01

    Here we present an autopsy case of chronic traumatic encephalopathy (CTE) in a 36-year-old man. He had a history of febrile seizures at the age of four and was severely demented at age 10 when he was admitted to a mental hospital. He had suffered repetitive self-harm, such as frequent banging of the head on the wall in his hospital record, but he had no clear history between the ages of four and ten. Autopsy revealed global cerebral atrophy, including the basal ganglia, thalamus, hippocampus, amygdala, mammilary bodies and lateral geniculate bodies. This case showed typical pathological features of CTE. Phosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs) and neuropil threads (NT) we are widely distributed in the brain, especially in the depth of the cerebral sulci. NFT and NT were also found in the basal ganglia, thalamus, amygdala and brainstem. Scanty β-amyloid deposits were found in the motor and sensory cortices, but α-synuclein was completely negative in the brain. This example showed that CTE can occur in young ages and that even children can experience CTE dementia.

  4. Brain Pathology in Myotonic Dystrophy: When Tauopathy Meets Spliceopathy and RNAopathy

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    Marie-Laure eCaillet-Boudin

    2014-01-01

    Full Text Available Myotonic dystrophy (DM of type 1 and 2 (DM1 and DM2 are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulator factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration.

  5. Roles of tau pathology in the locus coeruleus (LC) in age-associated pathophysiology and Alzheimer's disease pathogenesis: Potential strategies to protect the LC against aging.

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    Satoh, Akiko; Iijima, Koichi M

    2017-12-21

    The locus coeruleus (LC) is the noradrenaline (norepinephrine, NE)-containing nucleus in the brainstem and innervates into widespread brain regions. This LC-NE system plays a critical role in a variety of brain functions, including attention, arousal, emotion, cognition, and the sleep-wake cycle. The LC is one of the brain regions vulnerable to the occurrence of neurofibrillary tangles (NFTs), which is associated with "primary age-related tauopathy (PART)" that describes the pathology commonly observed in the brains of aged individuals. In Alzheimer's disease (AD), the LC is one of the first places to develop NFTs, which may act as a seed for subsequent spreading of the pathology throughout the brain upon amyloid-β (Aβ) accumulation. As AD progresses, significant neuron loss occurs in the LC. Moreover, LC neurodegeneration is not only a consequence of AD, but also drives clinical and pathological manifestations of AD, such as microglial dysregulation, sleep disturbance, cognitive decline, and neurovascular dysfunction. Therefore, prevention of NFT pathology and neuron loss in the LC-NE system is critical for suppressing the progression of AD. We propose that targeting aging itself may be a proactive intervention against age-associated changes in the LC. Such an approach could open the way for novel interventions against age-associated neurodegenerative disorders, in particular, AD. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer’s disease

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    Darrell Sawmiller

    2017-04-01

    Full Text Available Alzheimer’s disease (AD, a progressive neurodegenerative disorder, is linked to oxidative stress, altered amyloid precursor protein (APP proteolysis, tau hyperphosphorylation and the accumulation of amyloid-β (Aβ plaques and neurofibrillary tangles (NFT. A growing body of evidence suggests that mitochondrial dysfunction can be a key promoter of all of these pathologies and predicts that restoration of mitochondrial function might be a potential therapeutic strategy for AD. Therefore, in the present study, we tested the beneficial effect of a nutraceutical formulation Nutrastem II (Nutra II, containing NT020 (a mitochondrial restorative and antioxidant proprietary formulation and pyrroloquinolinequinone (PQQ, a stimulator of mitochondria biogenesis in 5XFAD transgenic mice. Animals were fed Nutra II for 12 weeks, starting at 3 months of age, after which behavioral and neuropathological endpoints were determined. The data from behavioral test batteries clearly revealed that dietary supplementation of Nutra II effectively ameliorated the motor deficiency and cognitive impairment of 5XFAD mice. In addition, Nutra II also protected mitochondrial function in 5XFAD mice brain, as evidenced by declined ROS levels and membrane hyperpolarization, together with elevated ATP levels and respiratory states. Interestingly, while Nutra II treatment only slightly reduced soluble Aβ42 levels, this formulation significantly impacted tau metabolism, as shown by reduced total and phosphorylated tau levels of 5XFAD mouse brain. Taken together, these preclinical findings confirm that mitochondrial function may be a key treatment target for AD and that Nutra II should be further investigated as a potential candidate for AD therapy.

  7. Cerebrospinal fluid apolipoprotein E levels in subacute sclerosing panencephalitis.

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    Yüksel, Deniz; Ichiyama, Takashi; Yilmaz, Deniz; Anlar, Banu

    2012-04-01

    Neurofibrillary tangles (NFTs) have been shown in 20% of subacute sclerosing panencephalitis (SSPE) cases. NFTs contain paired helical filaments formed by hyperphosphorylated tau. The intraneuronal tau metabolism and the rate of formation of paired helical filaments can be regulated by interactions between tau and isoforms of Apolipoprotein E (Apo E). Tau binds in vitro to Apo E3, interferes with the hyperphosphorylation of tau and may reduce the formation of NFTs. We investigated cerebrospinal fluid (CSF) Apo E levels in SSPE (n=37) and age-matched control (n=38) groups. The median level of total Apo E and Apo E4 were lower in the SSPE than the control group (p<0.001 and p=0.002). On the other hand, median Apo E3 level (0.28±0.23 μg/ml) was higher in the SSPE group (p<0.001). Such elevated levels of ApoE3 might play a role in controlling the formation of NFTs in SSPE. Because NFT-associated neurodegeneration is a slow process, comparison of the long-term clinical course of SSPE cases with high and low Apo E3 levels might provide further understanding or the role of these molecules in this disease, and help the planning of neuroprotective treatment. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  8. High-content siRNA screening of the kinome identifies kinases involved in Alzheimer's disease-related tau hyperphosphorylation

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    Gwinn Leslie

    2010-01-01

    Full Text Available Abstract Background Neurofibrillary tangles (NFT, a cardinal neuropathological feature of Alzheimer's disease (AD that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments. Results We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2, the dual-specificity tyrosine-(Y-phosphorylation regulated kinase 1A (DYRK1A, and the A-kinase anchor protein 13 (AKAP13 on tau phosphorylation at the 12E8 epitope (serine 262/serine 356. We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways. Conclusions These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.

  9. Local Somatodendritic Translation and Hyperphosphorylation of Tau Protein Triggered by AMPA and NMDA Receptor Stimulation

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    Shunsuke Kobayashi

    2017-06-01

    Full Text Available Tau is a major component of the neurofibrillary tangles (NFT that represent a pathological hallmark of Alzheimer's disease (AD. Although generally considered an axonal protein, Tau is found in the somato-dendritic compartment of degenerating neurons and this redistribution is thought to be a trigger of neurodegeneration in AD. Here, we show the presence of tau mRNA in a dendritic ribonucleoprotein (RNP complex that includes Ca2+-calmodulin dependent protein kinase (CaMKIIα mRNA and that is translated locally in response to glutamate stimulation. Further, we show that Tau mRNA is a component of mRNP granules that contain RNA-binding proteins, and that it interacts with Myosin Va, a postsynaptic motor protein; these findings suggest that tau mRNA is transported into dendritic spines. We also report that tau mRNA localized in the somato-dendritic component of primary hippocampal cells and that a sub-toxic concentration of glutamate enhances local translation and hyperphosphorylation of tau, effects that are blocked by the gluatamatergic antagonists MK801 and NBQX. These data thus demonstrate that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA and N-methyl-d-aspartate (NMDA stimulation redistributes tau to the somato-dendritic region of neurons where it may trigger neurodegeneration.

  10. GSK-3β and Memory Formation

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    Akihiko eTakashima

    2012-04-01

    Full Text Available In Alzheimer’s disease (AD, tau hyperphosphorylation and neurofibrillary tangle (NFT formation are strongly associated with dementia. Memory impairment is a characteristic, early symptom of AD. Glycogen synthase kinase 3 β (GSK-3β, which is activated in response to amyloid β (Aβ formation, and the normal process of aging, hyperphosphorylates tau present in the NFTs. Furthermore, activation of GSK-3β inhibits synaptic long-term potentiation (LTP through tau. It is therefore likely, that activation of GSK-3β is responsible for the memory problems seen in both advanced age, and AD. Indeed, inhibition of GSK-3 by lithium halts the progression of symptoms in patients with mild cognitive impairment (MCI. However, long-term treatment of lithium increases the risk of dementia in old age, in bipolar patients. To understand the role of GSK-3β in brain function, we analyzed memory formation in GSK-3β heterozygote, knockout mice. Results indicate that these mice show impaired memory reconsolidation. It would seem that activation of GSK-3β is required for memory maintenance, with a higher requirement as animals age, and the volume of memory increases. This in turn causes exaggerated activation of GSK-3β, leading to memory problems, and the formation of NFTs.

  11. Alzheimer's Disease and the Eye

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    Richard A. Armstrong

    2009-01-01

    Full Text Available Dementia, including Alzheimer's disease (AD, is a major disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of β-amyloid (Aβ in the form of senile plaques (SP and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT. A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA, colour vision and visual fields; changes in pupillary response to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP; and disturbances of complex visual functions such as reading, visuospatial function, and in the naming and identification of objects. Many of these changes are controversial with conflicting data in the literature and no ocular or visual feature can be regarded as particularly diagnostic of AD. In addition, some pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. The optometrist has a role in helping a patient with AD, if it is believed that signs and symptoms of the disease are present, so as to optimize visual function and improve the quality of life.

  12. Oral Administration of Thioflavin T Prevents Beta Amyloid Plaque Formation in Double Transgenic AD Mice.

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    Sarkar, Sumit; Raymick, James; Ray, Balmiki; Lahiri, Debomoy K; Paule, Merle G; Schmued, Larry

    2015-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult-onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40 mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT-treated mice. Both Aβ-40 and Aβ-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of Aβ plaques in brain.

  13. Tau deposition drives neuropathological, inflammatory and behavioral abnormalities independently of neuronal loss in a novel mouse model.

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    Cook, Casey; Kang, Silvia S; Carlomagno, Yari; Lin, Wen-Lang; Yue, Mei; Kurti, Aishe; Shinohara, Mitsuru; Jansen-West, Karen; Perkerson, Emilie; Castanedes-Casey, Monica; Rousseau, Linda; Phillips, Virginia; Bu, Guojun; Dickson, Dennis W; Petrucelli, Leonard; Fryer, John D

    2015-11-01

    Aberrant tau protein accumulation drives neurofibrillary tangle (NFT) formation in several neurodegenerative diseases. Currently, efforts to elucidate pathogenic mechanisms and assess the efficacy of therapeutic targets are limited by constraints of existing models of tauopathy. In order to generate a more versatile mouse model of tauopathy, somatic brain transgenesis was utilized to deliver adeno-associated virus serotype 1 (AAV1) encoding human mutant P301L-tau compared with GFP control. At 6 months of age, we observed widespread human tau expression with concomitant accumulation of hyperphosphorylated and abnormally folded proteinase K resistant tau. However, no overt neuronal loss was observed, though significant abnormalities were noted in the postsynaptic scaffolding protein PSD95. Neurofibrillary pathology was also detected with Gallyas silver stain and Thioflavin-S, and electron microscopy revealed the deposition of closely packed filaments. In addition to classic markers of tauopathy, significant neuroinflammation and extensive gliosis were detected in AAV1-Tau(P301L) mice. This model also recapitulates the behavioral phenotype characteristic of mouse models of tauopathy, including abnormalities in exploration, anxiety, and learning and memory. These findings indicate that biochemical and neuropathological hallmarks of tauopathies are accurately conserved and are independent of cell death in this novel AAV-based model of tauopathy, which offers exceptional versatility and speed in comparison with existing transgenic models. Therefore, we anticipate this approach will facilitate the identification and validation of genetic modifiers of disease, as well as accelerate preclinical assessment of potential therapeutic targets. © The Author 2015. Published by Oxford University Press.

  14. Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans.

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    Dickson, D W; Davies, P; Bevona, C; Van Hoeven, K H; Factor, S M; Grober, E; Aronson, M K; Crystal, H A

    1994-01-01

    In a neuropathological study of 81 brains of prospectively studied subjects of 80 years of age or older at the time of death, 13 cases (16%), including 4 men and 9 women, had hippocampal sclerosis (HpScl) affecting the vulnerable region of the hippocampus. In demented subjects of 80 years of age or older, the frequency of HpScl was even higher, 26%. Cases with HpScl had significantly fewer hippocampal senile plaques (SP) and neurofibrillary tangles (NFT) and parahippocampal NFT than cases without HpScl, but did not differ significantly in any of the other measured pathological parameters. Enzyme-linked analysis of synaptic protein immunoreactivity in a subset of 33 cases demonstrated significant decreases in the hippocampus, but not in frontal, temporal, parietal or parahippocampal cortices. All but 1 of the cases with HpScl had Blessed information, memory and concentration scores (BIMC) of 8 or more, and all were considered to be demented. In some patients memory disturbance was disproportionate to deficits in other cognitive areas. All but 4 of the cases with HpScl had many non-neuritic, amyloid plaques in the neocortex meeting NIA criteria for Alzheimer's disease (AD); however, given the advanced age of the subjects, amyloid plaques were considered to represent age-related cerebral amyloid deposition ("pathological aging") in most cases. Only 3 cases had both many SP and NFT in multiple cortical regions consistent with AD. Another case had brain stem and cortical Lewy bodies consistent with diffuse Lewy body disease (DLBD). A few ballooned neurons were present in the limbic cortices in 3 cases, including one case of dementia with argyrophilic grains (DAG) in limbic and orbital frontal and temporal cortices. The 8 cases without AD, DLBD or DAG included 4 cases in which no other obvious cause of dementia was detected and 4 cases in which HpScl was accompanied by either multiple cerebral infarcts or leukoencephalopathy, or both, that could have contributed to

  15. γ-Aminobutyric Acid (GABA) Production and Angiotensin-I Converting Enzyme (ACE) Inhibitory Activity of Fermented Soybean Containing Sea Tangle by the Co-Culture of Lactobacillus brevis with Aspergillus oryzae.

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    Jang, Eun Kyeong; Kim, Nam Yeun; Ahn, Hyung Jin; Ji, Geun Eog

    2015-08-01

    To enhance the γ-aminobutyric acid (GABA) content, the optimized fermentation of soybean with added sea tangle extract was evaluated at 30°C and pH 5.0. The medium was first inoculated with Aspergillus oryzae strain FMB S46471 and fermented for 3 days, followed by the subsequent inoculation with Lactobacillus brevis GABA 100. After fermentation for 7 days, the fermented soybean showed approximately 1.9 g/kg GABA and exhibited higher ACE inhibitory activity than the traditional soybean product. Furthermore, several peptides in the fraction containing the highest ACE inhibitory activity were identified. The novel fermented soybean enriched with GABA and ACE inhibitory components has great pharmaceutical and functional food values.

  16. Diversity, distribution and floral specificity of tangle-veined flies (Diptera: Nemestrinidae in north west Patagonia, Argentina Diversidad, distribución y especificidad floral de nemestrínidos (Diptera en el noroeste de la Patagonia, Argentina

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    MARIANO DEVOTO

    2006-03-01

    Full Text Available Tangle-veined flies (Nemestrinidae constitute a primitive and rather widespread family among Diptera. The genus Trichophthalma occurs in Australia and South America and is the only one in the family with a typically Gondwanian, disjoint distribution. The ecology and distribution of most southern South American species of this genus remains virtually unknown. We studied the diversity, distribution and flower specificity of flower-visiting species of the genus Trichophthalma in the temperate forests of southern South America in ten sites along an east-west rainfall gradient (37-40°S on the eastern slope of the Andes. We recorded nine species of Trichophthalma, which showed an overlapped distribution along the gradient and different degrees of floral specificity. Three species are reported for Argentina for the first time and three are first recorded as flower visitors to the local flora. Our results show that while in southern Africa tangle-veined flies are engaged in highly specialized pollination interactions with long-tubed species, the Trichophthalma spp. of Patagonia share their flowers with a diverse and rather unspecialized visitor fauna among which several species of flies, bees and birds are presentLos nemestrínidos constituyen una familia de Dípteros primitiva y de amplia distribución. El género Trichophthalma se encuentra en Australia y Sudamérica y es el único en la familia con una distribución disjunta típicamente gondwánica. La ecología y distribución de la mayoría de las especies sudamericanas permanecen virtualmente desconocidas. Estudiamos la diversidad, distribución y especificidad floral de las especies del género Trichophthalma de los bosques templados del sur de Sudamérica en diez sitios ubicados a lo largo de un gradiente de precipitación este-oeste (37-40°S sobre la vertiente occidental de los Andes. Registramos nueve especies de Trichophthalma, las cuales mostraron una distribución superpuesta a lo largo

  17. An inconspicuous, conspicuous new species of Asian pipesnake, genus Cylindrophis (Reptilia: Squamata: Cylindrophiidae), from the south coast of Jawa Tengah, Java, Indonesia, and an overview of the tangled taxonomic history of C. ruffus (Laurenti, 1768).

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    Kieckbusch, Max; Mecke, Sven; Hartmann, Lukas; Ehrmantraut, Lisa; O'shea, Mark; Kaiser, Hinrich

    2016-03-20

    We describe a new species of Cylindrophis currently known only from Grabag, Purworejo Regency, Jawa Tengah Pro-vince (Central Java), Java, Indonesia. Cylindrophis subocularis sp. nov. can be distinguished from all congeners by the presence of a single, eponymous subocular scale between the 3rd and 4th or 4th and 5th supralabial, preventing contact between the 4th or 5th supralabial and the orbit, and by having the prefrontal in narrow contact with or separated from the orbit. We preface our description with a detailed account of the tangled taxonomic history of the similar and putatively wide-ranging species C. ruffus, which leads us to (1) remove the name Scytale scheuchzeri from the synonymy of C. ruffus, (2) list the taxon C. rufa var. javanica as species inquirenda, and (3) synonymize C. mirzae with C. ruffus. We provide additional evidence to confirm that the type locality of C. ruffus is Java. Cylindrophis subocularis sp. nov. is the second species of Asian pipesnake from Java.

  18. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

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    Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

    2017-11-27

    Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

  19. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

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    Laura Llorach-Pares

    2017-11-01

    Full Text Available Computer-aided drug discovery/design (CADD techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A–G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer’s disease (AD, a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT. Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β and Casein kinase 1 delta (CK1δ, CK1D or KC1D, and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A and cdc2-like kinases (CLK1. This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

  20. 3D culture models of Alzheimer's disease: a road map to a "cure-in-a-dish".

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    Choi, Se Hoon; Kim, Young Hye; Quinti, Luisa; Tanzi, Rudolph E; Kim, Doo Yeon

    2016-12-09

    Alzheimer's disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.

  1. Dysregulation of cellular calcium homeostasis in Alzheimer's disease: bad genes and bad habits.

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    Mattson, M P; Chan, S L

    2001-10-01

    Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasticity, and the regulation of various metabolic pathways. The findings reviewed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer's disease (AD). Associations between the pathological hallmarks ofAD (neurofibrillary tangles [NFT] and amyloid plaques) and perturbed cellular calcium homeostasis have been established in studies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the beta-amyloid precursor protein (APP) and presenilins on neuronal plasticity and survival have provided insight into the molecular cascades that result in synaptic dysfunction and neuronal degeneration in AD. Central to the neurodegenerative process is the inability of neurons to properly regulate intracellular calcium levels. Increased levels of amyloid beta-peptide (Abeta) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnerable to apoptosis and excitotoxicity. Subtoxic levels of Abeta may induce synaptic dysfunction by impairing multiple signal transduction pathways. Presenilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links between aberrant calcium regulation and altered APP processing are emerging. Environmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual activity (bad habits); in each case, the environmental factor impacts on neuronal calcium homeostasis. Low calorie diets and intellectual activity may guard against AD by stimulating production of neurotrophic factors and chaperone proteins. The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic

  2. Clinicopathologic correlates in the oldest-old: Commentary on "No disease in the brain of a 115-year-old woman".

    Science.gov (United States)

    Giannakopoulos, Panteleimon; Bouras, Constantin; Hof, Patrick R

    2008-08-01

    den Dunnen et al. [den Dunnen, W.F.A., Brouwer, W.H., Bijlard, E., Kamphuis, J., van Linschoten, K., Eggens-Meijer, E., Holstege, G., 2008. No disease in the brain of a 115-year-old woman. Neurobiol. Aging] had the opportunity to follow up the cognitive functioning of one of the world's oldest woman during the last 3 years of her life. They performed two neuropsychological evaluations at age 112 and 115 that revealed a striking preservation of immediate recall abilities and orientation. In contrast, working memory, retrieval from semantic memory and mental arithmetic performances declined after age 112. Overall, only a one-point decrease of MMSE score occurred (from 27 to 26) reflecting the remarkable preservation of cognitive abilities. The neuropathological assessment showed few neurofibrillary tangles (NFT) in the hippocampal formation compatible with Braak staging II, absence of amyloid deposits and other types of neurodegenerative lesions as well as preservation of neuron numbers in locus coeruleus. This finding was related to a striking paucity of Alzheimer disease (AD)-related lesions in the hippocampal formation. The present report parallels the early descriptions of rare "supernormal" centenarians supporting the dissociation between brain aging and AD processes. In conjunction with recent stereological analyses in cases aged from 90 to 102 years, it also points to the marked resistance of the hippocampal formation to the degenerative process in this age group and possible dissociation between the occurrence of slight cognitive deficits and development of AD-related pathologic changes in neocortical areas. This work is discussed in the context of current efforts to identify the biological and genetic parameters of human longevity.

  3. THE VISININ-LIKE PROTEINS VILIP-1 AND VILIP-3 IN ALZHEIMER’S DISEASE – OLD WINE IN NEW BOTTLES

    Directory of Open Access Journals (Sweden)

    Karl Heinz Braunewell

    2012-02-01

    Full Text Available The neuronal Ca2+-sensor proteins, VILIP-1 and VILIP-3 (gene names VSNL1 and HPCAL1, have been implicated in the etiology of Alzheimer’s disease (AD. In AD brains, expression of proteins and mRNA is down-regulated. Reduced hippocampal VILIP-1 mRNA levels correlate with the content of neurofibrillary tangles (NFT and amyloid plaques - the pathological characteristics of AD, and with the mini mental state exam (MMSE, a test for cognitive impairment. Recently, VILIP-1 was identified as a cerebrospinal fluid (CSF biomarker for AD. Its increased CSF levels correlate with levels of Abeta, tau, ApoE4, and reduced MMSE scores. Moreover, genome-wide association studies (GWAS show association of VSNL1 and HPCAL1 loci with AD+P (+psychosis and late onset AD (LOAD, respectively. VILIP-1 is involved in pathological mechanisms of altered Ca2+-homeostasis, including enhanced tau phosphorylation and cell death, depending on co-expression with the neuroprotective Ca2+ buffer calbindin D28K. VILIP-1 affect pathways, such as cyclic nucleotide signalling and dendritic growth, as well as nicotinergic modulation of neuronal network activity, both of which regulate synaptic plasticity and cognition. The interaction partner of VILIP-1, alpha4beta2 nicotinic acetylcholine receptor, is severely reduced in AD. Comparatively little is known about VILIP-3. It interferes with MAPK signaling and interacts with cytochrome b5, an enzyme belonging to the plasma membrane redox system (PMRS. The PMRS, which provides electrons for the recycling of antioxidants, is impaired in AD. A current hypothesis is that the reduced expression of VILIPs in AD reflects Ainduced down-regulation of their expression, and indicates selective vulnerability of subpopulations of neurons, such as hippocampal interneurons. The down-regulation attenuates neuronal signal pathways regulating the functions of dendrites and neuroplasticity, and as a consequence, this may contribute to the cognitive

  4. Colocalization of phosphorylated forms of WAVE1, CRMP2, and tau in Alzheimer's disease model mice: Involvement of Cdk5 phosphorylation and the effect of ATRA treatment.

    Science.gov (United States)

    Watamura, Naoto; Toba, Junya; Yoshii, Aya; Nikkuni, Miyu; Ohshima, Toshio

    2016-01-01

    Alzheimer's disease (AD) is the most common type of dementia among the elderly. Neurofibrillary tangles (NFTs), a major pathological hallmark of AD, are composed of tau protein that is hyperphosphorylated by cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK3β). NFTs also contain Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) and collapsin response-mediator protein 2 (CRMP2). Although Cdk5 is known to phosphorylate tau, WAVE1, and CRMP2, the significance of this with respect to NFT formation remains to be elucidated. This study examines the involvement of phosphorylated (p-) CRMP2 and WAVE1 in p-tau aggregates using a triple-transgenic (3×Tg; APPswe/PS1M146V/tauP301L) AD mouse model. First, we verified the colocalization of p-WAVE1 and p-CRMP2 with aggregated hyperphosphorylated tau in the hippocampus at 23 months of age. Biochemical analysis revealed the inclusion of p-WAVE1, p-CRMP2, and tau in the sarkosyl-insoluble fractions of hippocampal homogenates. To test the significance of phosphorylation of these proteins further, we administered all-trans-retinoic acid (ATRA) to the 3×Tg mice, which downregulates Cdk5 and GSK3β activity. In ATRA-treated mice, fewer and smaller tau aggregates were observed compared with non-ATRA-treated mice. These results suggest the possibility of novel therapeutic target molecules for preventing tau pathology. © 2015 Wiley Periodicals, Inc.

  5. Natural products against Alzheimer's disease: Pharmaco-therapeutics and biotechnological interventions.

    Science.gov (United States)

    Dey, Abhijit; Bhattacharya, Raktim; Mukherjee, Anuradha; Pandey, Devendra Kumar

    Alzheimer's disease (AD) is a severe, chronic and progressive neurodegenerative disease associated with memory and cognition impairment ultimately leading to death. It is the commonest reason of dementia in elderly populations mostly affecting beyond the age of 65. The pathogenesis is indicated by accumulation of the amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFT) in brain tissues and hyperphosphorylation of tau protein in neurons. The main cause is considered to be the formation of reactive oxygen species (ROS) due to oxidative stress. The current treatment provides only symptomatic relief by offering temporary palliative therapy which declines the rate of cognitive impairment associated with AD. Inhibition of the enzyme acetylcholinesterase (AChE) is considered as one of the major therapeutic strategies offering only symptomatic relief and moderate disease-modifying effect. Other non-cholinergic therapeutic approaches include antioxidant and vitamin therapy, stem cell therapy, hormonal therapy, use of antihypertensive or lipid-lowering medications and selective phosphodiesterase (PDE) inhibitors, inhibition of β-secretase and γ-secretase and Aβ aggregation, inhibition of tau hyperphosphorylation and intracellular NFT, use of nonsteroidal anti-inflammatory drugs (NSAIDs), transition metal chelators, insulin resistance drugs, etanercept, brain-derived neurotrophic factor (BDNF) etc. Medicinal plants have been reported for possible anti-AD activity in a number of preclinical and clinical trials. Ethnobotany, being popular in China and in the Far East and possibly less emphasized in Europe, plays a substantial role in the discovery of anti-AD agents from botanicals. Chinese Material Medica (CMM) involving Chinese medicinal plants has been used traditionally in China in the treatment of AD. Ayurveda has already provided numerous lead compounds in drug discovery and many of these are also undergoing clinical investigations. A number of medicinal plants

  6. New tangles in the auxin signaling web

    Science.gov (United States)

    Wright, R. Clay

    2015-01-01

    Plants use auxin to relay critical information that shapes their growth and development. Auxin perception and transcriptional activation are mediated by the degradation of Aux/IAA repressor proteins. Degradation of Aux/IAAs relieves repression on Auxin Response Factors (ARFs), which bind DNA sequences called Auxin Response Elements (AuxREs). In most higher plant genomes, multiple paralogs exist for each part of the auxin nuclear signaling pathway. This potential combinatorial diversity in signaling pathways likely contributes to the myriad of context-specific responses to auxin. Recent structures of several domains from ARF proteins have exposed new modes of ARF dimerization, new models for ARF-AuxRE specificity, and the strong likelihood of larger order complexes formed by ARF and Aux/IAA homo- and heteromultimerization. Preliminary experiments support a role for these novel interactions in planta, further increasing the potential architectural complexity of this seemingly simple pathway. PMID:25750737

  7. Cell competition: pirates on the tangled bank.

    Science.gov (United States)

    Green, Douglas R

    2010-04-02

    Competition by stem cells for occupation of a limited niche is a well-described phenomenon. Two recent studies highlight competition between hematopoietic stem cells based on p53. These findings have implications for both normal homeostasis and tumorigenesis. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  8. Intractable Tangles in the Bird Family Tree.

    Science.gov (United States)

    Roberts, Roland G

    2015-08-01

    Rapid sequential speciation events can outpace the fixation of genetic variants, resulting in a family tree that lacks clear branching patterns. A new study of bird genomes reveals such an explosive super-radiation that may coincide with the mass extinction at the end of the Cretaceous period.

  9. "It Takes at Least Two to Tangle"

    Science.gov (United States)

    Walker, Janice M.

    2010-01-01

    Despite past lessons, book-banning continues to exist at all levels within our democratic society. This case presents a realistic scenario when the school district, facing a book challenge by a concerned parent, responds by removing the book from the library. On the basis of a true story, the study features a parent of an elementary child…

  10. New tangles in the auxin signaling web.

    Science.gov (United States)

    Wright, R Clay; Nemhauser, Jennifer L

    2015-01-01

    Plants use auxin to relay critical information that shapes their growth and development. Auxin perception and transcriptional activation are mediated by the degradation of Aux/IAA repressor proteins. Degradation of Aux/IAAs relieves repression on Auxin Response Factors (ARFs), which bind DNA sequences called Auxin Response Elements (AuxREs). In most higher plant genomes, multiple paralogs exist for each part of the auxin nuclear signaling pathway. This potential combinatorial diversity in signaling pathways likely contributes to the myriad of context-specific responses to auxin. Recent structures of several domains from ARF proteins have exposed new modes of ARF dimerization, new models for ARF-AuxRE specificity, and the strong likelihood of larger order complexes formed by ARF and Aux/IAA homo- and heteromultimerization. Preliminary experiments support a role for these novel interactions in planta, further increasing the potential architectural complexity of this seemingly simple pathway.

  11. Gout and Metabolic Syndrome: a Tangled Web.

    Science.gov (United States)

    Thottam, Gabrielle E; Krasnokutsky, Svetlana; Pillinger, Michael H

    2017-08-26

    The complexity of gout continues to unravel with each new investigation. Gout sits at the intersection of multiple intrinsically complex processes, and its prevalence, impact on healthcare costs, and association with important co-morbidities make it increasingly relevant. The association between gout and type 2 diabetes, hypertension, hyperlipidemia, cardiovascular disease, renal disease, and obesity suggest that either gout, or its necessary precursor hyperuricemia, may play an important role in the manifestations of the metabolic syndrome. In this review, we analyze the complex interconnections between gout and metabolic syndrome, by reviewing gout's physiologic and epidemiologic relationships with its major co-morbidities. Increasing evidence supports gout's association with metabolic syndrome. More specifically, both human studies and animal models suggest that hyperuricemia may play a role in promoting inflammation, hypertension and cardiovascular disease, adipogenesis and lipogenesis, insulin and glucose dysregulation, and liver disease. Fructose ingestion is associated with increased rates of hypertension, weight gain, impaired glucose tolerance, and dyslipidemia and is a key driver of urate biosynthesis. AMP kinase (AMPK) is a central regulator of processes that tend to mitigate against the metabolic syndrome. Within hepatocytes, leukocytes, and other cells, a fructose/urate metabolic loop drives key inhibitors of AMPK, including AMP deaminase and fructokinase, that may tilt the balance toward metabolic syndrome progression. Preliminary evidence suggests that agents that block the intracellular synthesis of urate may restore AMPK activity and help maintain metabolic homeostasis. Gout is both an inflammatory and a metabolic disease. With further investigation of urate's role, the possibility of proper gout management additionally mitigating metabolic syndrome is an evolving and important question.

  12. Asthma and cystic fibrosis: A tangled web.

    LENUS (Irish Health Repository)

    Kent, Brian D

    2014-03-01

    Successfully diagnosing concomitant asthma in people with cystic fibrosis (CF) is a challenging proposition, and the utility of conventional diagnostic criteria of asthma in CF populations remains uncertain. Nonetheless, the accurate identification of individuals with CF and asthma allows appropriate tailoring of therapy, and should reduce the unnecessary use of asthma medication in broader CF cohorts. In this review, we discuss the diagnostic challenge posed by asthma in CF, both in terms of clinical evaluation, and of interpretation of pulmonary function testing and non-invasive markers of airway inflammation. We also examine how the role of cross-sectional thoracic imaging in CF and asthma can assist in the diagnosis of asthma in these patients. Finally, we critically appraise the evidence base behind the use of asthma medications in CF populations, with a particular focus on the use of inhaled corticosteroids and bronchodilators. As shall be discussed, the gaps in the current literature make further high-quality research in this field imperative. Pediatr Pulmonol. 2014; 49:205-213. © 2014 Wiley Periodicals, Inc.

  13. Tangled in a sparse spider web

    DEFF Research Database (Denmark)

    Dimitrov, Dimitar Stefanov; Lopardo, Lara; Giribet, Gonzalo

    2012-01-01

    In order to study the tempo and the mode of spider orb web evolution and diversification, we conducted a phylogenetic analysis using six genetic markers along with a comprehensive taxon sample. The present analyses are the first to recover the monophyly of orb-weaving spiders based solely on DNA ...

  14. Pathology of the superior colliculus in chronic traumatic encephalopathy

    OpenAIRE

    Richard A. Armstrong; McKee, Ann C.; Cairns, Nigel J.

    2017-01-01

    PURPOSE: To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. METHODS: The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic ...

  15. Antisense-mediated Exon Skipping Decreases Tau Protein Expression: A Potential Therapy For Tauopathies

    OpenAIRE

    Sud, Reeteka; Geller, Evan T.; Schellenberg, Gerard D.

    2014-01-01

    In Alzheimer's disease, progressive supranuclear palsy, and a number of other neurodegenerative diseases, the microtubule associated protein tau aggregates to form intracellular neurofibrillary tangles and glial tangles, abnormal structures that are part of disease pathogenesis. Disorders with aggregated tau are called tauopathies. Presently, there are no disease-modifying treatments for this disease class. Tau is encoded by the MAPT gene. We propose that reducing MAPT expression and thus the...

  16. Cultivo hidropônico da alface empregando substratos: uma alternativa a NFT? Growing lettuce plants in hydroponics using substrates: an alternative for the NFT?

    Directory of Open Access Journals (Sweden)

    Jerônimo L. Andriolo

    2004-12-01

    Full Text Available Foi desenvolvido um dispositivo experimental para o cultivo da alface em sistema hidropônico fechado empregando substratos. As bancadas foram constituídas por telhas de cimento amianto, cujos canais foram preenchidos com brita basáltica. Sobre a brita foram dispostos os substratos, formando uma camada de 0,05 m de altura, com a superfície revestida com filme de polietileno opaco branco. As mudas foram produzidas em bandejas de poliestireno e plantadas em orifícios feitos sobre a superfície do filme de polietileno. Uma solução nutritiva completa foi fornecida diariamente, por meio de tubos gotejadores localizados na superfície da camada de substrato e abaixo do filme de polietileno. A solução drenada foi recolhida por gravidade para dentro do reservatório principal. Foram conduzidos dois experimentos, no período entre 16 de maio e 24 de junho e 1º e 28 de outubro de 2003, empregando as cultivares Regina e Mimosa e os substratos areia média e substrato orgânico Plantmax® Folhosas HA. No decorrer dos experimentos, houve diminuição dos valores de pH da solução nutritiva, tendo sido feita apenas uma correção em cada um dos experimentos. No dia mais quente do experimento de primavera, a temperatura foi mais elevada na areia, sem diferença significativa do substrato orgânico, cuja média situou-se 5,4ºC acima da temperatura da solução nutritiva e 0,4ºC acima daquela do ar. As médias mais elevadas das variáveis de crescimento e desenvolvimento foram observadas no substrato orgânico no outono, enquanto, na primavera, foram constatadas nos tratamentos tendo areia como substrato. O emprego dos substratos permitiu uma redução em torno de 92,4% no tempo de funcionamento da motobomba e simplificou tanto o manejo da fertirrigação como os controles da solução nutritiva.An experimental set-up to grow lettuce plants in a closed hydroponic growing system using substrates was made up and tested. Commercial fibber cement tiles were used as growing beds, in which gullies were filled with basaltic gravel. Substrates were laid out over the gravel in a 0.05 m layer depth and covered with a white polyethylene sheet. Lettuce plantlets from polystyrene nursery trays were planted in gaps made by cuttings on the polyethylene sheet. A complete nutrient solution was delivered daily to plants, by means of a drip irrigation system placed just bellow the polyethylene sheet and over the substrate layer. The nutrient solution running off from gullies was conducted back to the catchment tank. Two experiments were carried out, from May 16 to June 24, and from October 1th to October 28, 2003, using the lettuce cultivars Regina and Mimosa, and sand and the organic substrate Plantmax® Folhosas HA as growing media. The pH values of the nutrient solution decreased, but only one pH correction was made during each one of the experimental periods. On the hottest day of the spring experiment, temperature was higher in sand, but did not differ significantly from the organic substrate. Average values reached 5.4ºC above that of the nutrient solution and 0.4ºC above that of the air. Growth and development plant variables showed higher values in plants growing in the organic substrate in autumn, whereas in spring they were recorded on plants grown in sand. The substrates allowed a 92.4% reduction in the time during which the pump was switched on, leading to a simplification in practices of fertigation and control of the nutrient solution.

  17. Amyloid beta1–42 and the phoshorylated tau threonine 231 in brains of aged cynomolgus monkeys (Macaca fascicularis)

    DEFF Research Database (Denmark)

    Darusman, Huda Shalahudin; Gjedde, Albert; Sajuthi, Dondin

    2014-01-01

    Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarke...

  18. Aberrant myelinated neurites in the anterior horns of a patient with amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Troost, D.; Louwerse, E. S.; de Jong, J. M.; van Leersum, G. S.; van Raalte, J. A.

    1989-01-01

    A case of amyotrophic lateral sclerosis revealed the classical pathologic features of ALS, i.e. neuronal loss in the anterior horns and pyramidal tract degeneration. In addition to the pathological hallmarks of Alzheimer's disease, senile plaques, neurofibrillary tangles and granulovacuolar changes

  19. Glia in Alzheimer's disease and aging: Molecular mechanisms underlying astrocyte and microglia reactivity

    NARCIS (Netherlands)

    Orre, A.M.

    2014-01-01

    Alzheimer’s disease (AD) is the most common form of dementia in our society. The disease is characterized by pathological hallmarks such as Amyloid beta (Aß) plaques and neurofibrillary tangles. These pathological changes are associated with neuronal dysfunction and severe cognitive impairment. In

  20. Relationship of aluminum to Alzheimer's disease.

    Science.gov (United States)

    Perl, D P

    1985-01-01

    Alzheimer's disease is a progressive degenerative brain disease of unknown etiology, characterized by the development of large numbers of neurofibrillary tangles and senile plaques in the brain. Aluminum salts may be used experimentally to produce lesions which are similar, but not identical, to the neurofibrillary tangle. Although some studies have reported increased amounts of aluminum in the brains of Alzheimer's disease victims, these bulk analysis studies have been difficult to replicate and remain controversial. Using scanning electron microscopy with X-ray spectrometry, we have investigated this question on the cellular level. We have identified abnormal accumulations of aluminum within neurons derived from Alzheimer's disease patients containing neurofibrillary tangles. Similar accumulations have been detected in the numerous neurofibrillary tangle-bearing neurons seen in the brains of the indigenous native population of the island of Guam who suffer from amyotrophic lateral sclerosis and parkinsonism with dementia. Epidemiologic evidence strongly suggests a causal role for local environmental conditions relating to availability of aluminum, calcium, and magnesium. In view of the fact that a major consequence of acid rain is the liberation of large amounts of aluminum in bioavailable forms, concerns are raised about possible human health risks of this environmental phenomenon. PMID:4076080

  1. Cardiovascular risk factors and future risk of Alzheimer's disease

    NARCIS (Netherlands)

    R.F.A.G. de Bruijn (Renée); M.A. Ikram (Arfan)

    2014-01-01

    textabstractAlzheimer's disease (AD) is the most common neurodegenerative disorder in elderly people, but there are still no curative options. Senile plaques and neurofibrillary tangles are considered hallmarks of AD, but cerebrovascular pathology is also common. In this review, we summarize

  2. Untangling the Mystery of Alzheimer's Disease-Understanding ...

    Indian Academy of Sciences (India)

    http://www.ias.ac.in/article/fulltext/reso/007/02/0033-0045. Keywords. Neurodegenerative disorder; senile dementia; -amyloid plaques; neurofibrillary tangles. Author Affiliations. Sovan Sarkar1 Anupam Choudhury T N Avinash. II MSc - Biotechnology School of Biotechnology Madurai Kamaraj University Madurai 625021, ...

  3. Neuropathological Alterations in Alzheimer Disease

    Science.gov (United States)

    Serrano-Pozo, Alberto; Frosch, Matthew P.; Masliah, Eliezer; Hyman, Bradley T.

    2011-01-01

    The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI. PMID:22229116

  4. Effect of carbon dioxide enrichment on radish production using Nutrient Film Technique (NFT)

    Science.gov (United States)

    Mackowiak, C. L.; Ruffe, L. M.; Yorio, N. C.; Wheeler, R. M.

    1994-01-01

    Radish plants (Raphanus sativus L. cvs. Cherry Belle, Giant White Globe, and Early Scarlet Globe) were grown in four different CO2 enriched environments, 0.04, 0.10, 0.50, and 1.00 kPa (400, 1000, 5000, 10000 ppm). Cultivar responses to CO2 treatments varied, where cv. Cherry Belle showed no significant response to CO2 enrichment, cv. Giant White Globe was moderately affected and Early Scarlet Globe was strongly affected. Enrichment at 0.10 kPa led to greater root dry matter (DM) than 1.00 kPa for cv. Giant White Glove, whereas 0.10 kPa produced greater storage root, shoot, and root DM than 1.00 kPa for cv. Early Scarlet Globe. The data suggest that 1.00 kPa CO2 may be detrimental to the growth of certain radish cultivars. Root:shoot ratios tended to increase with increasing CO2 concentration. Water use efficiency (g biomass/kg H2O) increased with increasing CO2 enrichment, up to 0.5 kPa but then declined at the 1.00 kPa treatment. The total nitric acid used to maintain nutrient solution pH was lowest at the 1.00 kPa treatment as well, suggesting a decreased demand of nutrients by the plants at the highest CO2 level.

  5. Lettuce growth and water consumption in NFT hydroponic system using brackish water

    Directory of Open Access Journals (Sweden)

    Hammady R. Soares

    2015-07-01

    Full Text Available The qualitative aspects of water, such as the preparation or replenishment of the nutrient solution, are critical to the success of hydroponic crops. Therefore, the aim of this study was to evaluate the behavior of “Americana” lettuce (cv. Tainá under increasing levels of saline stress (0.2 - control, 1.2, 2.2, 3.2, 4.2 and 5.2 dS m-1, replenishing the evapotranspiration with brackish water in Experiment I and supply water (0.2 dS m-1 in Experiment II, both used in the preparation of the nutrient solution. In both experiments, the treatments were arranged in a randomized block design, with six treatments and four replicates. Shoot fresh matter, shoot dry matter and leaf area in Experiment I suffered reductions of 15.22, 12.67 and 15.6% per unit increase of EC, respectively. In Experiment II, reductions of 8.01, 6.90 and 8.14% were observed for the same variables, respectively. In Experiments I and II, linear decrease in water consumption due to the increase in salinity was observed, with reductions of 8.83 and 5.63% for each unit increase of electrical conductivity of water when the evapotranspiration was replenished using brackish and supply water, respectively.

  6. The dynamic behaviour of salinity changes in a closed NFT growing.

    NARCIS (Netherlands)

    Gieling, Th.H.; Bontsema, J.; Lukasse, L.J.S.

    1994-01-01

    In the Netherlands a law will enforce the use of closed growing systems in greenhouses. A project is initiated at IMAG-DLO to introduce ion-selective measurement and controlled injection of singular liquid nutrients in closed growing systems. As part of this project step and impulse response tests

  7. Nutrients balance and tip burn incidence in lettuce from hydroponic system - NFT

    OpenAIRE

    Claudio Pereira; Ana Maria R Junqueira; Sebastião Alberto de Oliveira

    2005-01-01

    Para avaliar o efeito do balanço nutricional na incidência de queima de bordos em plantas de alface, conduzidas em hidroponia, foi instalado um experimento em área da Universidade de Brasília, de outubro/2001 a junho/2002. Na primeira etapa do experimento, foram adotadas quatro condutividades elétricas (0,5; 1,5; 2,5 e 4,0 mS.cm-1) para avaliar a que apresentaria a maior incidência de queima de bordos. Em uma segunda etapa, adotou-se a concentração de 4,0 mS.cm-1 e aplicações foliares de três...

  8. A Changing Perspective on the Role of Neuroinflammation in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Donna M. Wilcock

    2012-01-01

    Full Text Available Alzheimer's disease (AD is a complex, neurodegenerative disorder characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain. Glial cells, particularly microglial cells, react to the presence of the amyloid plaques and neurofibrillary tangles producing an inflammatory response. While once considered immunologically privileged due to the blood-brain barrier, it is now understood that the glial cells of the brain are capable of complex inflammatory responses. This paper will discuss the published literature regarding the diverse roles of neuroinflammation in the modulation of AD pathologies. These data will then be related to the well-characterized macrophage phenotypes. The conclusion is that the glial cells of the brain are capable of a host of macrophage responses, termed M1, M2a, M2b, and M2c. The relationship between these states and AD pathologies remains relatively understudied, yet published data using various inflammatory stimuli provides some insight. It appears that an M1-type response lowers amyloid load but exacerbates neurofibrillary tangle pathology. In contrast, M2a is accompanied by elevated amyloid load and appears to ameliorate, somewhat, neurofibrillary pathology. Overall, it is clear that more focused, cause-effect studies need to be performed to better establish how each inflammatory state can modulate the pathologies of AD.

  9. Tau proteins in the cerebrospinal fluid of patients with subacute sclerosing panencephalitis.

    Science.gov (United States)

    Yuksel, Deniz; Yilmaz, Deniz; Uyar, Neval Y; Senbil, Nesrin; Gurer, Yavuz; Anlar, Banu

    2010-06-01

    Neurodegenerative diseases characterized by cytoskeletal deformation and neurofibrillary tangles are associated with altered levels of tau and related proteins in cerebrospinal fluid (CSF). Neuronal or glial fibrillary tangles have been shown in 20% of subacute sclerosing panencephalitis (SSPE) patients. We therefore investigated CSF samples from 60 newly diagnosed SSPE and 31 neurological control patients for total tau (t-tau), phosphorylated tau (p-tau), and S100-B levels by ELISA. There was no difference between patient and control groups in t-tau and S100-B levels. p-Tau was lower in the SSPE group (p=0.009). Past history of measles infection, measles immunization status, latent period between measles and onset of SSPE, duration of symptoms, frequency of myoclonia, neurological deficit index, stage and progression rate of the disease, CSF glucose levels and cell counts, CSF and serum measles IgG titer, distribution of lesions on brain magnetic resonance imaging were not related to t-tau, p-tau and S100-B levels. Mental status and age were negatively correlated with t-tau, and male gender and EEG abnormalities were associated with higher t-tau levels. The levels of tau proteins in our patients suggest there is no, or only scarce and immature, neurofibrillary tangle formation in SSPE. Autopsy studies showing neurofibrillary tangles might have examined older patients with longer disease and more parenchymal involvement. Copyright (c) 2009 Elsevier B.V. All rights reserved.

  10. Pathology of the Superior Colliculus in Chronic Traumatic Encephalopathy.

    Science.gov (United States)

    Armstrong, Richard A; McKee, Ann C; Cairns, Nigel J

    2017-01-01

    To investigate neuropathological changes in the superior colliculus in chronic traumatic encephalopathy. The densities of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, astrocytic tangles, and neuritic plaques, together with abnormally enlarged neurons, typical neurons, vacuolation, and frequency of contacts with blood vessels, were studied across the superior colliculus from pia mater to the periaqueductal gray in eight chronic traumatic encephalopathy and six control cases. Tau-immunoreactive pathology was absent in the superior colliculus of controls but present in varying degrees in all chronic traumatic encephalopathy cases, significant densities of tau-immunoreactive neurofibrillary tangles, NT, or dot-like grains being present in three cases. No significant differences in overall density of the tau-immunoreactive neurofibrillary tangles, neuropil threads, dot-like grains, enlarged neurons, vacuoles, or contacts with blood vessels were observed in control and chronic traumatic encephalopathy cases, but chronic traumatic encephalopathy cases had significantly lower mean densities of neurons. The distribution of surviving neurons across the superior colliculus suggested greater neuronal loss in intermediate and lower laminae in chronic traumatic encephalopathy. Changes in density of the tau-immunoreactive pathology across the laminae were variable, but in six chronic traumatic encephalopathy cases, densities of tau-immunoreactive neurofibrillary tangles, neuropil threads, or dot-like grains were significantly greater in intermediate and lower laminae. Pathological changes were not correlated with the distribution of blood vessels. The data suggest significant pathology affecting the superior colliculus in a proportion of chronic traumatic encephalopathy cases with a laminar distribution which could compromise motor function rather than sensory analysis.

  11. Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study.

    Directory of Open Access Journals (Sweden)

    Claudia K Suemoto

    2017-03-01

    Full Text Available Clinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis.In this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y. Cognitive function was investigated using the Clinical Dementia Rating (CDR and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE; neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI. Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD, and 35% of vascular dementia (VaD. Neurofibrillary tangles (NFTs, hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20-1.46, IQCODE (β = 0.14, 95% CI 0.13-0.16, and NPI (β = 1.74, 95% CI = 1.33-2.16. Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with

  12. Tauopathy PET and amyloid PET in the diagnosis of chronic traumatic encephalopathies: studies of a retired NFL player and of a man with FTD and a severe head injury.

    Science.gov (United States)

    Mitsis, E M; Riggio, S; Kostakoglu, L; Dickstein, D L; Machac, J; Delman, B; Goldstein, M; Jennings, D; D'Antonio, E; Martin, J; Naidich, T P; Aloysi, A; Fernandez, C; Seibyl, J; DeKosky, S T; Elder, G A; Marek, K; Gordon, W; Hof, P R; Sano, M; Gandy, S

    2014-09-16

    Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [(18)F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [(18)F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [(18)F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [(18)F]-T807 PET imaging revealed striatal and nigral [(18)F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [(18)F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [(18)F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [(18)F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented

  13. Clinicopathologic studies in cognitively healthy aging and Alzheimer's disease: relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype.

    Science.gov (United States)

    Berg, L; McKeel, D W; Miller, J P; Storandt, M; Rubin, E H; Morris, J C; Baty, J; Coats, M; Norton, J; Goate, A M; Price, J L; Gearing, M; Mirra, S S; Saunders, A M

    1998-03-01

    To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Washington University Alzheimer's Disease Research Center, St Louis, Mo. Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E epsilon4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to epsilon4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to epsilon4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD

  14. An aluminum-based rat model for Alzheimer's disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration.

    Science.gov (United States)

    Walton, J R

    2007-09-01

    In Alzheimer's disease (AD), oxidative damage leads to the formation of amyloid plaques while low PP2A activity results in hyperphosphorylated tau that polymerizes to form neurofibrillary tangles. We probed these early events, using brain tissue from a rat model for AD that develops memory deterioration and AD-like behaviors in old age after chronically ingesting 1.6 mg aluminum/kg bodyweight/day, equivalent to the high end of the human dietary aluminum range. A control group consumed 0.4 mg aluminum/kg/day. We stained brain sections from the cognitively-damaged rats for evidence of amyloid plaques, neurofibrillary tangles, aluminum, oxidative damage, and hyperphosphorylated tau. PP2A activity levels measured 238.71+/-17.56 pmol P(i)/microg protein and 580.67+/-111.70 pmol P(i)/microg protein (paluminum-loading occurs in some aged rat neurons as in some aged human neurons; (2) aluminum-loading in rat neurons is accompanied by oxidative damage, hyperphosphorylated tau, neuropil threads, and granulovacuolar degeneration; and (3) amyloid plaques and neurofibrillary tangles were absent from all rat brain sections examined. Known species difference can reasonably explain why plaques and tangles are unable to form in brains of genetically-normal rats despite developing the same pathological changes that lead to their formation in human brain. As neuronal aluminum can account for early stages of plaque and tangle formation in an animal model for AD, neuronal aluminum could also initiate plaque and tangle formation in humans with AD.

  15. Aluminum and Alzheimer's disease, a personal perspective after 25 years.

    Science.gov (United States)

    Perl, Daniel P; Moalem, Sharon

    2006-01-01

    It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer's disease and other related disorders.

  16. A FORAY INTO THE TANGLE OF GLOBALIZATION MEASUREMENT

    Directory of Open Access Journals (Sweden)

    PhD Iulia LUPU

    2013-06-01

    Full Text Available The concerns over globalization and its impact on the different aspects of life amplified over the recent years and generated the need to measure this phenomenon so as to know its effects and to get prepared to manage them. This paper makes a critical presentation of the main indicators that measure the phenomenon of globalization and selected one indicator, seemingly the most comprehensive, and applied it to Romania in order to see its rank when comparing with other countries, according to the values of the indicator and its components.

  17. Calculator programs guide directionally drilled wells through tangled Thums lease

    Energy Technology Data Exchange (ETDEWEB)

    Clark, D.D.; Barth, J.W.

    1983-10-01

    Over 900 wells have been directionally drilled in the Long Beach Unit of the East Wilmington field from four man-made islands and land-based drilling sites. As more wells are added to each site, the planning of new well courses has become more complex. The hand-held calculator, with Long Beach Unit-developed programs, has been an aid in laying out new wells which avoid existing cased bore holes. The hand-held calculator method also prevented unnecessary commercial computer runs of well plats from surface locations that prove impossible or impractical to drill. With the use of these programs the optimum well course can be designed, reducing drilling and design costs.

  18. The tangle of space and time in human cognition.

    Science.gov (United States)

    Núñez, Rafael; Cooperrider, Kensy

    2013-05-01

    Everyday concepts of duration, of sequence, and of past, present, and future are fundamental to how humans make sense of experience. In culture after culture, converging evidence from language, co-speech gesture, and behavioral tasks suggests that humans handle these elusive yet indispensable notions by construing them spatially. Where do these spatial construals come from and why do they take the particular, sometimes peculiar, spatial forms that they do? As researchers across the cognitive sciences pursue these questions on different levels--cultural, developmental--in diverse populations and with new methodologies, clear answers will depend upon a shared and nuanced set of theoretical distinctions. Time is not a monolith, but rather a mosaic of construals with distinct properties and origins. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Conservation through community: An attempt to untangle a tangled word.

    Directory of Open Access Journals (Sweden)

    Deeraj Koul

    2014-04-01

    Full Text Available Conservation is not something that can be thrust upon a community, and neither can it be labelled as a measure to take away a people’s rights and nor can it be used as a force to make others adhere to rules and laws from outside; by outside I mean you and me and your or my Government. I am not writing to highlight that conservation should not happen with the community but I do believe that older community bonds are broken or they have started to brake and the ways implied earlier no longer hold in the field. Most of us are still hanging on to older approaches to community conservation but the younger generation in a community has moved beyond, now it is rare to see a community come together for the sake of collective benefits and also when conservation measures take longer to deliver the fruits and the sustained release of impacts over a period of time it makes people forget the changes made to the immediate environment, except for a few visible ones. This too is forgotten with time until the cycle of destruction repeats itself. Previously, the community used to look at water, forests and other natural resources as common resources and they used to protect them, but the present generation does not understand common resources. In their terms it has to be yours or mine or else it is the Government’s. There is no fourth dimension, i.e. the common resource which used to be a main dimension of conservation. The vanishing concept of the common resource has brought about the biggest destruction ever. New ways of conservation have to be found as older traditional ways of conservation may still work in some places but they will be not adhered to by the majority. I am not saying this because community led work isn’t good enough, but because the community system was previously woven into social fabric and there was mutual dependence. However, the social fabric has changed a lot over recent years and so has traditional community bonding. The west lost it a long time ago but other regions are catching up very quickly; community bonds are getting weaker and weaker and other ways of social bonding are taking over and we all are still struggling to solve problems through our narrow prism of community. We need to broaden it. I don’t mean that community shouldn’t be involved, it is the only way, but we need to understand the psyche of the community and try new ways to involve it. I hope I have not confused you and that you will continue reading. For everyone the mantra of conservation is through community and almost all conservation activities revolve around one particular community. However, I feel there is a problem with the way it is projected and the percentage success rate is very low. In other words, in a world were two brothers do not have same level of thinking and the same approach to a single issue, how can we expect a community to work together on a single focused agenda and hold on to it for a long period at a time when people have started to weigh everything on a scale of personal gain. Also, since conservation is a time-consuming process it is quite likely that the efforts of a community and its initial enthusiasm will fade over time. On this point a lot of people will try to pounce on me and try to prove me wrong with data and by showcasing successful community level projects. I do not deny that there are lots of success stories but are we getting the percentage of results that should have been achieved by now with so many NGOs, aid agencies and government efforts coming together? What is the success rate of these projects? An officer from the forest department once told me that in the last 30 years in India so many plantations have been made through community that no space would be available for plantations if all the work had born results. He may have exaggerated or he may be referring to poor implementation but there might still be some truth to his word. Also, I do expect the same kind of results around the world with some variations, since so much money has been spent through reforestation, community forestry. There seems to be a huge difference in conservation through community available on paper records and the reality on the ground, meaning that no matter how much money is spent, conservation has a low success rate and we are still persisting with ideas that have a very low percentage of success. In a community project a lot of management committees are formed, a forest committee, a watershed committee, a management committee; people participate and committees are formed but most of the committees become defunct over a period of time or they remain but are inactive. What are the reasons behind this? Maybe there is very little personal stake or low interest due to the high probability of getting bad reputation in the eyes of people if a community member tries to ensure that the system is adhered to. As the needs of people are unlimited and resources are limited a conflict of interest is bound to arise. I agree that other factors such as local politics etc. are also responsible, and I also agree that we need to persist in conservation through community as any other option will be suicidal. Some will try to argue that for any project the work to be undertaken is decided by the community and even the priority of work is decided by the community, at each step the community is involved from initiation to completion. But how many of us see sustained community support and adherence from initiation to completion and beyond. As we know from the human tendency most times we humans get involved keenly only when we see direct benefits, and not through indirect benefits or co-benefits. Thus, in order to make everyone get involved each person has to see some kind of a personal stake in the project, otherwise only a few will persist and others will not. We as conservationists think that it is the duty of a community to protect itself. Conservation will not be successful because we think that the community should protect itself. Even within a community there are different views and they will come together but will only disintegrate with time. To see how well a project will work I believe that we first need to analyse how much the members of the community are dependent on each other, how much the community is woven into the social fabric and its bonds, how much the community is not affected by my political factionalism. And if the community lacks in the above then we have to change the way conservation is conducted. Community approaches like collective thinking but direct individual benefits need to be incorporated more into the programmes so that better results can be achieved, by direct benefit I don’t mean monetary benefit but giving every individual a sense of belief that whatever conservation effort he has done at his level is his own, it is his creation and he is the master of its destiny. I also trust that we are witnessing new social bonding’s which are independent of regional background, politics, colour, rich and poor differentiation, taking shape and blooming as social media groups, they have a power to evolve a new thinking, bring change and develop a new form of common resource concept which can take conservation of globalised community to a new platform. These are not the only ways but surely other ways of uniting a community need to be found in order to generate a truly participatory approach.

  20. The Tangled Web of Taliban and Associated Movements

    Directory of Open Access Journals (Sweden)

    Greg Smith

    2009-01-01

    Full Text Available Following the devastating terrorist attacks of September 11, 2001,worldwide attention became focused on the Taliban and al-Qaida forcesin Afghanistan. Prior to the attacks, many people had never heard of the Taliban or their shar'ia-law style of government. Since 2001, manysplinter groups have formed in response to the continual United Statespresence in the region. Today, the term Taliban has been used to envelop several groups such as the Tehrik-i-Taliban Pakistan (TTP, the Haqqani Network (HQN and the Tehrik-eNifaz-e-Shariat-e-Mohammadi(TNSM. These groups make up the majority of fighters along the Afghanistan-Pakistan border. Many of these groups have been historicrivals for control of the region, but have since joined a loose alliance in response to United States and Pakistani Government actions in the Federally Administered Tribal Areas (FATA. This article examines the origins and operations of the Pakistani Taliban and associated groups. Particular attention will be given as to how these groups receive funding and support from each other through state sponsors such as Pakistan's Inter-Services Intelligence (ISI agency and non-state sponsors such as al-Qaida and Wahhabi idealists in Saudi Arabia, as well as arms supplies from Iran and potentially China.

  1. Quantifying the tangling of trajectories using the topological entropy

    Science.gov (United States)

    Candelaresi, S.; Pontin, D. I.; Hornig, G.

    2017-09-01

    We present a simple method to efficiently compute a lower limit of the topological entropy and its spatial distribution for two-dimensional mappings. These mappings could represent either two-dimensional time-periodic fluid flows or three-dimensional magnetic fields, which are periodic in one direction. This method is based on measuring the length of a material line in the flow. Depending on the nature of the flow, the fluid can be mixed very efficiently which causes the line to stretch. Here, we study a method that adaptively increases the resolution at locations along the line where folds lead to a high curvature. This reduces the computational cost greatly which allows us to study unprecedented parameter regimes. We demonstrate how this efficient implementation allows the computation of the variation of the finite-time topological entropy in the mapping. This measure quantifies spatial variations of the braiding efficiency, important in many practical applications.

  2. Tangled up in grief: Bob Dylan's songs of separation.

    Science.gov (United States)

    Smith, Keverne

    This article argues that much can be learned about the ways in which individuals grieve through a careful analysis of the presentation of loss in creative fiction, especially in terms of unconscious and uncensored responses presented indirectly through figurative language and structural patterns. It takes Bob Dylan's collection of songs about the anguish caused by lost love, Blood on the Tracks, as an example. An examination of the songs included in, and some rejected for, the album reveals developing responses to grief resulting from relationship breakdown, including the search for the absent one and for reconciliation; the intrusion of deep pain into everyday situations; the problem of infidelity and guilt; the attempt to reach a more detached perspective; the consequences of the pain becoming unbearable; and the attempt at a kind of closure. Taken together, the songs reveal how complex and contradictory responses to the agony of loss can be.

  3. [Ecology of vector systems: a tangle of complexity].

    Science.gov (United States)

    Rodhain, F

    2008-06-01

    The long co-evolutionary process between arthropods and microorganisms has resulted in a wide variety of relationships. One such relationship involves a wide range of infectious agents (virus, bacteria, protozoa, helminthes) that use blood-feeding arthropods (insects and mites) as vectors for transmission from one vertebrate to another. Transmission involves three components, i.e., microorganism, vector(s), and vertebrate host(s). Study under natural conditions has shown that the underlying mechanisms are extremely complex with circulation of the infectious agents depending on numerous conditions linked not only to bioecology but also to genetic factors in all three component populations. The role of arthropods sometimes goes beyond that of a transmitter of disease. In some cases they also serve as reservoirs or disseminators. In addition changes in the environment whether due to natural causes or human activities (e.g. pollution, agropastoralism, urbanization, transportation network development, and climate change) can have profound and rapid effects on the mechanisms underlying these vector systems. In short the ecology of vector systems closely reflects the extreme complexity of epidemiological studies on diseases caused by infectious agents depending on this type of transmission. As a result prediction of infectious risks and planning of preventive action are difficult. It appears obvious that a good understanding of vector systems in their natural context will require a truly ecological approach to the diseases that must be the focus of extremely close epidemiologic surveillance. Achieving this goal will necessitate more than the skills of physicians and veterinarians. It will require the contribution of specialists from a variety of fields such as microbiology, entomology, systematics, climatology, ecology, urbanism, social sciences, economic development, and many others.

  4. Host and Parasite Evolution in a Tangled Bank.

    Science.gov (United States)

    Betts, Alex; Rafaluk, Charlotte; King, Kayla C

    2016-11-01

    Most hosts and parasites exist in diverse communities wherein they interact with other species, spanning the parasite-mutualist continuum. These additional interactions have the potential to impose selection on hosts and parasites and influence the patterns and processes of their evolution. Yet, host-parasite interactions are almost exclusively studied in species pairs. A wave of new research has incorporated a multispecies community context, showing that additional ecological interactions can alter components of host and parasite fitness, as well as interaction specificity and virulence. Here, we synthesize these findings to assess the effects of increased species diversity on the patterns and processes of host and parasite evolution. We argue that our understanding of host-parasite interactions would benefit from a richer biotic perspective. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Investigation on metal elements in the brain tissues from DNTC patients

    Energy Technology Data Exchange (ETDEWEB)

    Ide-Ektessabi, Ari E-mail: h51167@sakura.kudpc.kyoto-u.ac.jp; Kawakami, Takuo; Ishihara, Ryoko; Mizuno, Yutaka; Takeuchi, Tohru

    2004-07-01

    Trace metallic elements in human cells play important roles in various cell functions as metalloprotein, metalloenzyme or metallic ions. Diffuse neurofibrillary tangles with calcification (DNTC) is an atypical dementia and is characterized pathologically by diffuse neurofibrillary tangles without senile plaques. In this study, X-ray fluorescence (XRF) spectroscopy using synchrotron radiation (SR) was applied to determine the distribution and density of the ultra-trace elements in the brain tissues from DTNC patients. This method made it possible to determine trace metallic elements non-destructively. The trace metallic elements (such as Ca, Fe, Zn, and Pb) in the brain tissues were examined. Two-dimension imaging of the elements and relative quantification of the elements in the brains were performed. The lead concentrations were observed in the calcified blood vessel in the brains with DNTC.

  6. Distribution of lead in the brain tissues from DNTC patients using synchrotron radiation microbeams

    Energy Technology Data Exchange (ETDEWEB)

    Ide-Ektessabi, Ari [International Innovation Center, Kyoto University, Kyoto (Japan); Ota, Yukihide [Department of Precision Engineering, Kyoto University, Yoshida Honnmachi, Sakyo-ku, Kyoto (Japan)]. E-mail: h51167@sakura.kudpc.kyoto-u.ac.jp; Ishihara, Ryoko [Department of Psychiatry, Nagoya University, Graduate School of Medicine, Nagoya (Japan); Mizuno, Yutaka [Obu Dementia Care Research and Training Center, Obu (Japan); Takeuchi, Tohru [Department of Psychiatry, Nagoya University, Graduate School of Medicine, Nagoya (Japan)

    2005-12-15

    Diffuse neurofibrillary tangles with calcification (DNTC) is a form of dementia with certain characteristics. Its pathology is characterized by cerebrum atrophy, calcification on globus pallidus and dentate nucleus and diffuse neurofibrillary tangles without senile plaques. In the present study brain tissues were prepared from patients with patients DNTC, calcified and non-calcified Alzheimer's disease (AD) patients. The brain tissues were examined non-destructively by X-ray fluorescence (XRF) spectroscopy using synchrotron radiation (SR) microbeams for trace metallic elements Ca, Fe, Cu, Zn and Pb. The XRF analysis showed that there were Pb concentrations in the calcified areas in the brain tissues with both DNTC and AD but there was none in those with non-calcified AD.

  7. Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation*

    OpenAIRE

    Sun,, Xiucong; Wu, De; Chen, Bin; Zhang, Zhuohua; Zhou, Weihui; Tong,; Yuan, Junying; Xia, Kun; Gronemeyer, Hinrich; Flavell, Richard A.; Song

    2011-01-01

    Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data s...

  8. Dementia Pugilistica with clinical features of Alzheimer's disease

    OpenAIRE

    Renata Areza-Fegyveres; Sergio Rosemberg; Castro, Rosa Maria R.P.S.; Claudia Sellitto Porto; Valéria Santoro Bahia; Paulo Caramelli; Ricardo Nitrini

    2007-01-01

    A 61-year-old ex-boxer presented with a three-year history of progressive memory decline. During a seven-year follow-up period, there was a continuous cognitive decline, very similar to that usually observed in Alzheimer's disease. Parkinsonian, pyramidal or cerebellar signs were conspicuously absent. Neuropathological examination revealed the typical features of dementia pugilistica: cavum septi pellucidi with multiple fenestrations, numerous neurofibrillary tangles in the cerebral isocortex...

  9. Frontal Cortex Neuropathology in Dementia Pugilistica

    OpenAIRE

    Saing, Tommy; Dick, Malcolm; Nelson, Peter T.; Kim, Ronald C; Cribbs, David H.; Head, Elizabeth

    2012-01-01

    AbstractDementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a “punch drunk” syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aβ), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who prese...

  10. Model Hirano Bodies Protect against Tau-Independent and Tau-Dependent Cell Death Initiated by the Amyloid Precursor Protein Intracellular Domain

    OpenAIRE

    Furgerson, Matthew; Fechheimer, Marcus; Furukawa, Ruth

    2012-01-01

    The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has ...

  11. A local insult of okadaic acid in wild-type mice induces tau phosphorylation and protein aggregation in anatomically distinct brain regions

    OpenAIRE

    Baker, Si?n; G?tz, J?rgen

    2016-01-01

    In Alzheimer?s disease (AD), the distribution and density of neurofibrillary tangles, a histological hallmark comprised predominately of phosphorylated tau protein, follows a distinct pattern through anatomically connected brain regions. Studies in transgenic mice engineered to regionally confine tau expression have suggested spreading of tau within neural networks. Furthermore, injection of protein lysates isolated from brains of transgenic mice or patients with tauopathies, including AD, we...

  12. Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer¿s Disease Evolution

    OpenAIRE

    Vergara, Cristina; Ordóñez-Gutiérrez, Lara; Wandosell, Francisco; Ferrer, I. M; Río, J. A. del; Gavín, Rosalina

    2014-01-01

    Alzheimer's disease (AD) is characterized by the presence of amyloid plaques mainly consisting of hydrophobic -amyloid peptide (A) aggregates and neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. A oligomers have been described as the earliest effectors to negatively affect synaptic structure and plasticity in the affected brains, and cellular prion protein (PrPC) has been proposed as receptor for these oligomers. The most widely accepted theory holds that the to...

  13. Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

    OpenAIRE

    Zussy, Charleine; Brureau, Anthony; Delair, Brice; Marchal, Stephane; Keller, Emeline; Ixart, Guy; Naert, Gaelle; Meunier, Johann; Chevallier, Nathalie; Maurice, Tangui; Givalois, Laurent

    2011-01-01

    Alzheimer's disease (AD) is a neurodegenerative pathology characterized by the presence of senile plaques and neurofibrillary tangles, accompanied by synaptic and neuronal loss. The major component of senile plaques is an amyloid β protein (Aβ) formed by pathological processing of the Aβ precursor protein. We assessed the time-course and regional effects of a single intracerebroventricular injection of aggregated Aβ fragment 25–35 (Aβ25-35) in rats. Using a combined biochemical, behavioral, a...

  14. Modulation der Alzheimer-Pathologie in transgenen Mausmodellen

    OpenAIRE

    Duma, Carmen Cecilia

    2009-01-01

    Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia. The neuropathological hallmarks of AD include extracellular deposits of the amyloid-ß peptide (Aß) and neurofibrillary tangles, composed of filamentous aggregates of hyperphosphorylated tau protein. To study AD pathogenesis, transgenic mice that overexpress human mutated amyloid precursor protein (APP) and/or mutated presenilin1/2 (PS1/2) have been generated. These models exhibit age-r...

  15. Anti-Amyloidogenic and Anti-Apoptotic Role of Melatonin in Alzheimer Disease

    OpenAIRE

    He, Hongwen; Dong, Weiguo; Huang, Fang

    2010-01-01

    Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by the presence of senile plaques, neurofibrillary tangles and neuronal loss. Amyloid-β protein (Aβ) deposition plays a critical role in the development of AD. It is now generally accepted that massive neuronal death due to apoptosis is a common characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. Melatonin i...

  16. Oxidative stress in Alzheimer disease

    OpenAIRE

    Gella, Alejandro; Durany, Nuria

    2009-01-01

    Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques ...

  17. Abstracts from the 7th Canadian Conference on Dementia (CCD) held in Vancouver, October 2013

    OpenAIRE

    Montgomery, S.; Wangsgaard, J.; Koenig, J.; Jeremy,; Pathak, K.; Jude, A.; Davidson, S.; Rice, J.; Cytryn, K.N.; Lungu, O.; Voyer, P.; Wilchesky, M.; Qian, W.; Schweizer, T.; Fischer, C.

    2013-01-01

    Background/Purpose: As of 2011, approximately 747,000 Canadians suffer from some form of dementia; Alzheimer?s disease (AD) is one such form. AD is a neurodegenerative disease characterized by significant neuronal death. Neuronal death has been associated with two pathophysiological features: 1) neurofibrillary tangles within the neurons, and 2) amyloid beta plaque formation between neurons. Excessive production of these two features is manifested by severe cognitive impairment. One of the mo...

  18. Efficacy and mechanism of action of novel synthetic fatty acids derivatives in a transgenic Drosophila melanogaster Model of a Alzheimer's disease

    OpenAIRE

    Mohaibes, Raheem J.

    2015-01-01

    - Introducció Alzheimer's disease (AD) is a neurodegenerative disorder characterized by early synaptic and late neuronal loss, affecting more than 26 million people worldwide. Among patients affected with dementia, more than half suffer from Alzheimer’s disease. The biggest risk factor for developing Alzheimer's disease is age. β-amyloid (Aβ) plaques and neurofibrillary p-Tau tangles accumulates in the brains of elderly patients playing a central role in the pathogenesis of ...

  19. Impact of antidiabetic substances to development of insulin resistance and neurodegenerative changes in mouse models of type 2 diabetes

    OpenAIRE

    Mikulášková, Barbora

    2014-01-01

    Numerous epidemiological and experimental studies have shown that patients suffering from metabolic disorders such as type 2 diabetes mellitus (TDM2), insulin resistance or obesity are at a higher risk of cognitive functions impairment and developing Alzheimer's disease (AD). Impairment of insulin signalling in the brain could contribute to two pathological changes which leads to AD development that include insoluble senile plaques and neurofibrillary tangles, containing an abnormally hyperph...

  20. Implications of Neuroimmunity in Alzheimer’s Disease: A Review

    OpenAIRE

    Katriel Lee

    2017-01-01

    AD is characterized cognitively by memory, problem-solving, and language difficulties. It is estimated that 5.4 million Americans currently have Alzheimer’s disease (AD). The cognitive difficulties in AD are reflected in the brain through the accumulation of amyloid-β (Aβ) in cerebral amyloid angiopathy (CAA), neurofibrillary tau tangles, neuronal tissue atrophy, and neuroinflammation, but the exact cause of AD is still in question. However, evidence suggests that differences in neuroimmune f...

  1. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

    OpenAIRE

    Jiao, S-S; Shen, L-L; C. Zhu; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D. G.; J. Tan; G?tz, J; Zhou, X-F; Wang, Y-J

    2016-01-01

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (A?) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against A?-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy ...

  2. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

    OpenAIRE

    Rachel E. Lackie; Rachel E. Lackie; Andrzej Maciejewski; Andrzej Maciejewski; Valeriy G. Ostapchenko; Jose Marques-Lopes; Wing-Yiu Choy; Martin L. Duennwald; Vania F. Prado; Vania F. Prado; Vania F. Prado; Vania F. Prado; Marco A. M. Prado; Marco A. M. Prado; Marco A. M. Prado

    2017-01-01

    The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degrada...

  3. Roles of Amyloid β-Peptide-Associated Oxidative Stress and Brain Protein Modifications in the Pathogenesis of Alzheimer's Disease and Mild Cognitive Impairment

    OpenAIRE

    Butterfield, D. Allan; Reed, Tanea; Newman, Shelley F.; Sultana, Rukhsana

    2007-01-01

    Oxidative stress has been implicated to play a crucial role in the pathogenesis of a number of diseases, including neurodegenerative disorders, cancer, and ischemia just to name a few. Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is recognized as the most common form of dementia. AD is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid β-peptide (Aβ), and ...

  4. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology

    OpenAIRE

    Lili-Naz eHazrati; Maria Carmela Tartaglia; Phedias eDiamandis; Karen eDavis; Green, Robin E. A.; Richard eWennberg; Wong, Janice C; Leo eEzerins; Tator, Charles H.

    2013-01-01

    Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer’s disease. Although the connection between repeated concussions and CTE-t...

  5. Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology

    OpenAIRE

    Hazrati, Lili-Naz; Tartaglia, Maria C.; Diamandis, Phedias; Karen D Davis; Green, Robin E.; Wennberg, Richard; Wong, Janice C; Ezerins, Leo; Tator, Charles H.

    2013-01-01

    Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussion...

  6. Optimization of microtubule affinity regulating kinase (MARK) inhibitors with improved physical properties

    Energy Technology Data Exchange (ETDEWEB)

    Sloman, David L.; Noucti, Njamkou; Altman, Michael D.; Chen, Dapeng; Mislak, Andrea C.; Szewczak, Alexander; Hayashi, Mansuo; Warren, Lee; Dellovade, Tammy; Wu, Zhenhua; Marcus, Jacob; Walker, Deborah; Su, Hua-Poo; Edavettal, Suzanne C.; Munshi, Sanjeev; Hutton, Michael; Nuthall, Hugh; Stanton, Matthew G. (Merck)

    2016-09-01

    Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer’s disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.

  7. Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature

    Science.gov (United States)

    Nelson, Peter T.; Alafuzoff, Irina; Bigio, Eileen H.; Bouras, Constantin; Braak, Heiko; Cairns, Nigel J.; Castellani, Rudolph J.; Crain, Barbara J.; Davies, Peter; Del Tredici, Kelly; Duyckaerts, Charles; Frosch, Matthew P.; Haroutunian, Vahram; Hof, Patrick R.; Hulette, Christine M.; Hyman, Bradley T.; Iwatsubo, Takeshi; Jellinger, Kurt A.; Jicha, Gregory A.; Kövari, Enikö; Kukull, Walter A.; Leverenz, James B.; Love, Seth; Mackenzie, Ian R.; Mann, David M.; Masliah, Eliezer; McKee, Ann C.; Montine, Thomas J.; Morris, John C.; Schneider, Julie A.; Sonnen, Joshua A.; Thal, Dietmar R.; Trojanowski, John Q.; Troncoso, Juan C.; Wisniewski, Thomas; Woltjer, Randall L.; Beach, Thomas G.

    2013-01-01

    Clinicopathologic correlation studies are critically important for the field of Alzheimer disease (AD) research. Studies on human subjects with autopsy confirmation entail numerous potential biases that affect both their general applicability and the validity of the correlations. Many sources of data variability can weaken the apparent correlation between cognitive status and AD neuropathologic changes. Indeed, most persons in advanced old age have significant non-AD brain lesions that may alter cognition independently of AD. Worldwide research efforts have evaluated thousands of human subjects to assess the causes of cognitive impairment in the elderly, and these studies have been interpreted in different ways. We review the literature focusing on the correlation of AD neuropathologic changes (i.e. β-amyloid plaques and neurofibrillary tangles) with cognitive impairment. We discuss the various patterns of brain changes that have been observed in elderly individuals to provide a perspective for understanding AD clinicopathologic correlation and conclude that evidence from many independent research centers strongly supports the existence of a specific disease, as defined by the presence of Aβ plaques and neurofibrillary tangles. Although Aβ plaques may play a key role in AD pathogenesis, the severity of cognitive impairment correlates best with the burden of neocortical neurofibrillary tangles. PMID:22487856

  8. Status of memory loss.

    LENUS (Irish Health Repository)

    Iyer, Parameswaran Mahadeva

    2012-01-01

    A 72-year-old woman presented with first onset of seizure with no prior history of cognitive dysfunction. EEG revealed focal non-convulsive status epilepticus. MRI brain showed a left temporal non-enhancing lesion. Temporal pole biopsy showed acute neuronal necrosis and astrocyte hyperplasia together with extensive amyloid plaques and neurofibrillary tangles. Perivascular oligodendroglial hyperplasia was present. Postmortem examination revealed extensive plaque and tangle disease. Perivascular oligodendroglial hyperplasia was limited to the left temporal area. The presence of focal perivascular oligodendroglial hyperplasia in the left temporal cortex, combined with extensive plaque and tangle disease may have contributed to the focal status epilepticus in this patient. Although the presence of focal perivascular oligodendroglial hyperplasia has been reported in cases of temporal lobe epilepsy, it has not been reported as a cause of seizure in patients with Alzheimer\\'s disease previously. Further studies for clinical-pathologic correlation would be required to confirm this hypothesis.

  9. Balanço nutricional e incidência de queima de bordos em alface produzida em sistema hidropônico - NFT Nutrients balance and tip burn incidence in lettuce from hydroponic system - NFT

    Directory of Open Access Journals (Sweden)

    Claudio Pereira

    2005-07-01

    Full Text Available Para avaliar o efeito do balanço nutricional na incidência de queima de bordos em plantas de alface, conduzidas em hidroponia, foi instalado um experimento em área da Universidade de Brasília, de outubro/2001 a junho/2002. Na primeira etapa do experimento, foram adotadas quatro condutividades elétricas (0,5; 1,5; 2,5 e 4,0 mS.cm-1 para avaliar a que apresentaria a maior incidência de queima de bordos. Em uma segunda etapa, adotou-se a concentração de 4,0 mS.cm-1 e aplicações foliares de três fontes de cálcio (CaCl2, CaB2® e CaNO3 com o objetivo de prevenir a ocorrência dos sintomas. Utilizou-se a formulação proposta por Castellane e Araújo em 1995, variando-se a concentração total dos nutrientes para atingir a condutividade elétrica desejada. O delineamento experimental foi em faixas, com quatro tratamentos e três repetições com 25 plantas cada. Foram avaliados a porcentagem de plantas com incidência de queima de bordos, teor foliar de macro e micronutrientes e peso fresco. Utilizou-se o sistema DRIS para análise dos teores foliares de nutrientes. Foi observado que a solução nutritiva de 4 mS.cm-1 apresentou porcentagem de plantas com queima de bordos superior às soluções com concentração de 2,5 e 1,5 mS.cm-1. Porém, não diferiu estatisticamente da solução com 0,5 mS.cm-1. Na segunda etapa, verificou-se que zinco foi o nutriente mais limitante, em função da alta concentração de boro, tendo sido o responsável pela incidência dos sintomas de queima de bordos. Desta forma, as pulverizações com cálcio, independentemente da fonte, não foram eficientes no controle ou redução dos sintomas.Aiming to evaluate the effect of nutrients balance in lettuce tip burn incidence, an experiment was carried out in Brasília, Brazil, from October 2001 until June 2002, in two phases. During the first phase four solution concentrations (0.5; 1.5; 2.5 and 4.0 mS.cm-1 were evaluated to determine the concentration with the highest percentage of tip burn. During the second phase, a solution concentration of 4,0 mS.cm-1 and foliar applications of three calcium sources (CaCl2, CaB2® and CaNO3 were applied to plants to prevent tip burn. Nutritive solution proposed by Castellane and Araújo in 1995 was used in both phases. The evaluated parameters were percentage of plants with tip burn incidence, leaf nutrient concentration and plant fresh weight. In the first trial the more concentrated (4,0 mS.cm-1 and the less concentrated (0,5 mS.cm-1 nutritive solution presented the highest percentage of plants with the symptoms. In the second trial, the zinc deficiency induced by boron high concentration, was responsible for the symptoms. This was the reason why calcium leaf application was not effective on reducing foliar symptoms.

  10. Longitudinal Assessment of Tau Pathology in Patients with Alzheimer's Disease Using [18F]THK-5117 Positron Emission Tomography.

    Directory of Open Access Journals (Sweden)

    Aiko Ishiki

    Full Text Available The formation of neurofibrillary tangles is believed to contribute to the neurodegeneration observed in Alzheimer's disease (AD. Postmortem studies have shown strong associations between the neurofibrillary pathology and both neuronal loss and the severity of cognitive impairment. However, the temporal changes in the neurofibrillary pathology and its association with the progression of the disease are not well understood. Tau positron emission tomography (PET imaging is expected to be useful for the longitudinal assessment of neurofibrillary pathology in the living brain. Here, we performed a longitudinal PET study using the tau-selective PET tracer [18F]THK-5117 in patients with AD and in healthy control subjects. Annual changes in [18F]THK-5117 binding were significantly elevated in the middle and inferior temporal gyri and in the fusiform gyrus of patients with AD. Compared to patients with mild AD, patients with moderate AD showed greater changes in the tau load that were more widely distributed across the cortical regions. Furthermore, a significant correlation was observed between the annual changes in cognitive decline and regional [18F]THK-5117 binding. These results suggest that the cognitive decline observed in patients with AD is attributable to the progression of neurofibrillary pathology. Longitudinal assessment of tau pathology will contribute to the assessment of disease progression and treatment efficacy.

  11. Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes.

    Science.gov (United States)

    Buée, L; Pérez-Tur, J; Leveugle, B; Buée-Scherrer, V; Mufson, E J; Loerzel, A J; Chartier-Harlin, M C; Perl, D P; Delacourte, A; Hof, P R

    1996-01-01

    Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E epsilon 4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the epsilon 4 allele frequency was 5.9%, the epsilon 3 allele frequency 88.2%, and the epsilon 2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the epsilon 4 allele, since all cases with senile plaques were epsilon 3/epsilon 3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the epsilon 2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC.

  12. Neuroinflammation and common mechanism in Alzheimer's disease and prion amyloidosis: amyloid-associated proteins, neuroinflammation and neurofibrillary degeneration

    NARCIS (Netherlands)

    Rozemuller, A.J.M.; Jansen, C.; Carrano, A.; van Haastert, E.S.; Hondius, D.; van der Vies, S.M.; Hoozemans, J.J.M.

    2012-01-01

    Background: In cases with a long (>1 year) clinical duration of prion disease, the prion protein can form amyloid deposits. These cases do not show accumulation of 4-kDa β-amyloid, which is observed in amyloid deposits in Alzheimer's disease (AD). In AD, amyloid is associated with inflammation and

  13. NASA Models of Space Radiation Induced Cancer, Circulatory Disease, and Central Nervous System Effects

    Science.gov (United States)

    Cucinotta, Francis A.; Chappell, Lori J.; Kim, Myung-Hee Y.

    2013-01-01

    effectiveness of radiation mitigator's. The NSRM- 2014 approaches to model radiation quality dependent lethality and NTE's will be described. CNS effects include both early changes that may occur during long space missions and late effects such as Alzheimer's disease (AD). AD effects 50% of the population above age 80-yr, is a degenerative disease that worsens with time after initial onset leading to death, and has no known cure. AD is difficult to detect at early stages and the small number of low LET epidemiology studies undertaken have not identified an association with low dose radiation. However experimental studies in mice suggest GCR may lead to early onset AD. We discuss modeling approaches to consider mechanisms whereby radiation would lead to earlier onset of occurrence of AD. Biomarkers of AD include amyloid beta (A(Beta)) plaques, and neurofibrillary tangles (NFT) made up of aggregates of the hyperphosphorylated form of the micro-tubule associated, tau protein. Related markers include synaptic degeneration, dentritic spine loss, and neuronal cell loss through apoptosis. Radiation may affect these processes by causing oxidative stress, aberrant signaling following DNA damage, and chronic neuroinflammation. Cell types to be considered in multi-scale models are neurons, astrocytes, and microglia. We developed biochemical and cell kinetics models of DNA damage signaling related to glycogen synthase kinase-3(Beta) (GSK3(Beta)) and neuroinflammation, and considered multi-scale modeling approaches to develop computer simulations of cell interactions and their relationships to A(Beta) plaques and NFTs. Comparison of model results to experimental data for the age specific development of A(Beta) plaques in transgenic mice will be discussed.

  14. Antioxidant and Cholinesterase Inhibitory Activities of Ethyl Acetate Extract ofTerminalia chebula: Cell-freeIn vitroandIn silicoStudies.

    Science.gov (United States)

    Rajmohamed, Mohamed Asik; Natarajan, Suganthy; Palanisamy, Premkumar; Abdulkader, Akbarsha Mohammad; Govindaraju, Archunan

    2017-10-01

    carried out to assess the neuroprotective effect of Terminalia chebula fruit and its phytoconstituent. Phytochemical analysis of fruit ethyl acetate extract of T. chebula (TCEA) showed the presence of alkaloid, cardiac glycoside, and tannin. TCEA showed potent acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities when compared to standard drug donepezil. Results of in vitro antioxidant assays revealed excellent free radical scavenging activity, reducing power, and potent metal-chelating activity. Gas chromatography-mass spectrum analysis illustrated the presence of 22 active compounds, among which methyl N-(N-benzyloxycarbonyl-beta-l-aspartyl)-beta-d-glucosaminide exhibited potent AChE and BuChE inhibition analyzed through in silico studies. Abbreviations used: AD: Alzheimer's disease; TCEA: Ethyl acetate extract of Terminalia chebula ; GC-MS: Gas chromatography-mass spectrum; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; AChE: Acetylcholinesterase; BuChE: Butyrylcholinesterase; NFT: Neurofibrillary tangles; Aμ: μ-amyloid; NSAIDS: Nonsteroidal anti-inflammatory drugs; FDA: Food and Drug Administration; RT: Room temperature; HCl: Hydrochloric acid; ATCI: Acetylthiocholine iodide; BTCI: Butyrylthiocholine iodide; BHT: Butylated hydroxytoluene; DPPH: 2,2-diphenyl-1-picrylhydrazyl; TCA: Trichloroacetic acid; GAE: Gallic acid equivalent; NICT: National Institute of Information and Communications Technology; 3D: Three-dimensional; PDB: Protein data bank; OPLS: Optimized potentials for liquid simulations; XP: Extra precision; SD: Standard deviation; ANOVA: Analysis of variance; EDTA: Ethylenediaminetetraacetic acid.

  15. Mechanisms of aluminum-induced neurodegeneration in animals: Implications for Alzheimer's disease.

    Science.gov (United States)

    Savory, John; Herman, Mary M; Ghribi, Othman

    2006-11-01

    For four decades the controversial question concerning a possible role for aluminum neurotoxicity in contributing to the pathogenesis of Alzheimer's disease has been debated, and studies by different investigators have yielded contradictory results. The lack of sensitivity to aluminum neurotoxicity in transgenic mouse models of Alzheimer's disease has not allowed the system to be used to explore important aspects of this toxicity. Rabbits are particularly sensitive to aluminum neurotoxicity and they develop severe neurological changes that are dependent on dose, age and route of administration. The most prominent feature induced by aluminum in rabbit brain is a neurofibrillary degeneration that shares some similarity with the neurofibrillary tangles found in Alzheimer's disease patients. In the present review we discuss data from our laboratory and others, on the effects of aluminum on behaviour, neurologic function and morphology, using aluminum administered to rabbits via different routes. Finally, we will examine data on the possible cellular mechanisms underlying aluminum neurotoxicity, and potential neuroprotective strategies against aluminum toxicity.

  16. Deregulated Cdk5 Activity Is Involved in Inducing Alzheimer’s Disease

    Science.gov (United States)

    Shukla, Varsha; Skuntz, Susan; Pant, Harish C.

    2012-01-01

    Alzheimer’s disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia and eventually, death of the affected individuals. Clinically, AD is characterized as late-onset, age-dependent cognitive decline due to loss of neurons in cortex and hippocampus. The pathologic corollary of these symptoms is the formation of senile plaques and neurofibrillary tangles. Senile plaques are formed due to accumulation of oligomeric amyloid beta (Aβ) forming fibrillary plaques. This occurs due to the amyloidogenic processing of the amyloid precursor protein (APP) by various secretases. On the other hand, neurofibrillary tangles are formed due to hyperphosphorylation of cytoskeleton proteins like tau and neurofilament. Both are hyperphosphorylated by cyclin-dependent kinase-5 (Cdk5) and are part of the paired helical filament (PHF), an integral part of neurofibrillary tangles. Unlike other cyclin-dependent kinases, Cdk5 plays a very important role in the neuronal development. Cdk5 gets activated by its neuronal activators p35 and p39. Upon stress, p35 and p39 are cleaved by calpain resulting in truncated products as p25 and p29. Association of Cdk5/p25 is longer and uncontrolled causing aberrant hyperphosphorylation of various substrates of Cdk5 like APP, tau and neurofilament, leading to neurodegenerative pathology like AD. Additionally recent evidence has shown increased levels of p25, Aβ, hyperactivity of Cdk5, phosphorylated tau and neurofilament in human AD brains. This review briefly describes the above-mentioned aspects of involvement of Cdk5 in the pathology of AD and at the end summarizes the advances in Cdk5 as a therapeutic target. PMID:23142263

  17. [The application of Gallyas-Braak stainings in pathologic diagnosis of neurodegenerative diseases].

    Science.gov (United States)

    Wang, Luning; Zhu, Mingwei; Li, Xianghong; Gui, Qiuping

    2002-02-01

    To evaluate the role of Gallyas silver staining in the diagnosis of neurodegenerative diseases. Modified Gallyas-Braak staining method was used to investigate samples of the brain and spinal cord of 22 cases with neurodegenerative disease including Alzheimer's disease (AD), Parkinson's diseas (PD), Pick's disease, diffuse Lewy body disease (DLBD), progressive supranuclear palsy (PSP), diagnosed by clinical and routine pathologic method. 10 cases without clinical symptoms and pathologic abnormalities of the nervous system served as control. As compared with Bodian staining, Gallyas-Braak staining demonstrated clearly neurofibrillary tangles in the hippocampus and the cortex of frontal and temperal lobe in all the cases with Alzheimer's disease, 6 cases with dementia of other causes and 3 normal aged. However, global neurofibrillary tangles in the midbrain and the basal ganglia were found only with Gallyas-Braak staining in 4 cases with both dementia and extrapyramidal features. In addition, tuft-shaped astrocytes were shown with this method in the motor cortex, basal ganglia, midbrain of the above 4 cases and astrocytic plaques in the same area in 2 cases of the 4 cases. In this connexion, pathologic findings in 2 of the 4 cases corresponded to PSP and those of the other two cases fufiled the diagnostic criteria of corticobasal degeneration (CBD) Oligodendroglial cytoplasmic inclusions in the white matter of the brain and the spinal cord were founded in 3 of the 4 cases with multiple system atrophy (MSA). This silver staining demonstrated as well a lot of argyrophilic grains in the neuropil of the temporal lobe and the hippocampus in one case with AD. Gallyas silver staining could better reveal not only Alzheimer-like neurofibrillary tangles but also different glial inclusions in other neurodegenerative diseases such as PSP, CBD and MSA. Consequently, it is of great value in the pathologic diagnosis and study of such degenerative diseases.

  18. Is the Aluminum Hypothesis Dead?

    Science.gov (United States)

    2014-01-01

    The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust. PMID:24806729

  19. Is the Aluminum Hypothesis dead?

    Science.gov (United States)

    Lidsky, Theodore I

    2014-05-01

    The Aluminum Hypothesis, the idea that aluminum exposure is involved in the etiology of Alzheimer disease, dates back to a 1965 demonstration that aluminum causes neurofibrillary tangles in the brains of rabbits. Initially the focus of intensive research, the Aluminum Hypothesis has gradually been abandoned by most researchers. Yet, despite this current indifference, the Aluminum Hypothesis continues to attract the attention of a small group of scientists and aluminum continues to be viewed with concern by some of the public. This review article discusses reasons that mainstream science has largely abandoned the Aluminum Hypothesis and explores a possible reason for some in the general public continuing to view aluminum with mistrust.

  20. Lysosomal Fusion Dysfunction as a Unifying Hypothesis for Alzheimer's Disease Pathology

    Directory of Open Access Journals (Sweden)

    Kristen E. Funk

    2012-01-01

    Full Text Available Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.

  1. An 85-year old male with levodopa-responsive parkinsonism followed by dementia and supranuclear ophthalmoplegia caused by alzheimer-type pathology without Lewy bodies.

    Science.gov (United States)

    Kasahata, Naoki; Hagiwara, Mariko; Kato, Hiroyuki; Nakamura, Ayako; Uchihara, Toshiki

    2014-01-01

    An 85-year-old man developed l-dopa responsive parkinsonism indistinguishable from Parkinson's disease and subsequent dementia, followed by supranuclear ophthalmoplegia and neck dorsiflexion at the terminal stage. Midbrain tegmentum and medial temporal lobe were atrophic on magnetic resonance imaging, while decreased blood flow was predominant in frontotemporal lobes, detected by 3D-SSP of 123I- IMP SPECT. Alzheimer-type pathology without Lewy body pathology was confirmed at autopsy. Substantia nigra showed mild degeneration and several neurofibrillary tangles without Lewy body pathology or progressive supranuclear palsy cytopathology. L-dopa responsive parkinsonism could be an initial manifestation of Alzheimer's disease, which should be included in the differential diagnosis.

  2. Microglia-Synapse Pathways: Promising Therapeutic Strategy for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Jingdun Xie

    2017-01-01

    Full Text Available The main hallmarks of Alzheimer’s disease (AD are extracellular deposits of amyloid plaques and intracellular accumulation of hyperphosphorylated neurofibrillary tangles (tau. However, the mechanisms underlying these neuropathological changes remain largely unclear. To date, plenty of studies have shown that microglia-mediated neuroinflammation contributes to the pathogenesis of AD, and the microglia-synapse pathways have been repeatedly identified as the crucial factor in the disease process. In this review, evidences from microglia and synapse studies are presented, and the role of microglia in the pathogenesis of AD, the contributing factors to synapse dysfunction, and the role and mechanisms of microglia-synapse pathways will be discussed.

  3. Alzheimer's 100th anniversary of death and his contribution to a better understanding of Senile dementia.

    Science.gov (United States)

    Engelhardt, Eliasz; Gomes, Marleide da Mota

    2015-02-01

    Initially the trajectory of the historical forerunners and conceptions of senile dementia are briefly presented, being highlighted the name of Alois Alzheimer who provided clinical and neuropathological indicators to differentiate a group of patients with Senile dementia. Alzheimer's examination of Auguste D's case, studied by him with Bielschowsky's silver impregnation technique, permitted to identify a pathological marker, the intraneuronal neurofibrillary tangles, characterizing a new disease later named after him by Kraepelin - Alzheimer's disease. Over the time this disorder became one of the most important degenerative dementing disease, reaching nowadays a status that may be considered as epidemic.

  4. GSK-3β, a pivotal kinase in Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Maria eLLorens-Martin

    2014-05-01

    Full Text Available Alzheimer disease (AD is the most common form of age-related dementia. The etiology of AD is considered to be multifactorial as only a negligible percentage of cases have a familial or genetic origin. Glycogen synthase kinase-3 (GSK-3 is regarded as a critical molecular link between the two histopathological hallmarks of the disease, namely senile plaques and neurofibrillary tangles. In this review, we summarize current data regarding the involvement of this kinase in several aspects of AD development and progression, as well as key observations highlighting GSK-3 as one of the most relevant targets for AD treatment.

  5. Evaluation of regional cerebral blood flow in patient with atypical senile dementia with asymmetrical calcification.

    Science.gov (United States)

    Shoyama, Masaru; Ukai, Satoshi; Shinosaki, Kazuhiro

    2015-12-01

    We report an 83-year-old woman with atypical senile dementia with Fahr-type calcification. Brain computed tomography demonstrated asymmetrical calcification predominant in the basal ganglia on the right side and pronounced diffuse cortical atrophy in the frontotemporal areas. The patient was clinically diagnosed with diffuse neurofibrillary tangles with calcification. Brain single photon emission computed tomography findings revealed that cerebral blood flow was reduced on the right side, as compared with the left side, in widespread areas. Hemispheric asymmetry in both calcification and cerebral blood flow suggests a relationship between calcification and vascular changes. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

  6. Alzheimer's 100th anniversary of death and his contribution to a better understanding of Senile dementia

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    2015-02-01

    Full Text Available Initially the trajectory of the historical forerunners and conceptions of senile dementia are briefly presented, being highlighted the name of Alois Alzheimer who provided clinical and neuropathological indicators to differentiate a group of patients with Senile dementia. Alzheimer's examination of Auguste D’s case, studied by him with Bielschowsky’s silver impregnation technique, permitted to identify a pathological marker, the intraneuronal neurofibrillary tangles, characterizing a new disease later named after him by Kraepelin – Alzheimer’s disease. Over the time this disorder became one of the most important degenerative dementing disease, reaching nowadays a status that may be considered as epidemic.

  7. ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Posado-Fernández, Adrián; Ahmadvand, Davoud

    2017-01-01

    The accumulation of extracellular amyloid-beta (Aβ) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Aβ deposition and/or accelerate its...... clearance. With the aid of a newly characterized monoclonal anti-Aβ antibody we constructed immunoPEGliposomes with high avidity for capturing Aβ in the periphery. The functionality of these vesicles in modulating Aβ uptake by both human brain capillary endothelial hCMEC/D3 cells (suppressing uptake...

  8. Alzheimer’s Disease: Mechanism and Approach to Cell Therapy

    Directory of Open Access Journals (Sweden)

    Takashi Amemori

    2015-11-01

    Full Text Available Alzheimer’s disease (AD is the most common form of dementia. The risk of AD increases with age. Although two of the main pathological features of AD, amyloid plaques and neurofibrillary tangles, were already recognized by Alois Alzheimer at the beginning of the 20th century, the pathogenesis of the disease remains unsettled. Therapeutic approaches targeting plaques or tangles have not yet resulted in satisfactory improvements in AD treatment. This may, in part, be due to early-onset and late-onset AD pathogenesis being underpinned by different mechanisms. Most animal models of AD are generated from gene mutations involved in early onset familial AD, accounting for only 1% of all cases, which may consequently complicate our understanding of AD mechanisms. In this article, the authors discuss the pathogenesis of AD according to the two main neuropathologies, including senescence-related mechanisms and possible treatments using stem cells, namely mesenchymal and neural stem cells.

  9. The Alzheimer myth and biomarker research in dementia.

    Science.gov (United States)

    Richard, Edo; Schmand, Ben; Eikelenboom, Piet; Westendorp, Rudi G; Van Gool, Willem A

    2012-01-01

    The focus of most of the research on Alzheimer's disease in the last decades has been on senile plaques and neurofibrillary tangles. The vast majority of patients with Alzheimer's disease are over 75 years of age, whereas most of the research focuses on younger subjects. To consider old-age dementia as a homogenous well-defined condition ignores the complexity of this condition and limits the development of new diagnostic methods, preventive strategies, or treatment strategies that could be widely applicable in daily practice in the majority of the older patients. The current research on biomarkers focuses on correlates of plaques and tangles, which are poor markers in older dementia subjects. Acknowledging that dementia in old age is an essentially different condition from dementia at relatively younger age is needed and should lead to new approaches in dementia research.

  10. Apparent diffusion coefficient measurements in progressive supranuclear palsy

    Energy Technology Data Exchange (ETDEWEB)

    Ohshita, T.; Oka, M.; Imon, Y.; Yamaguchi, S.; Mimori, Y.; Nakamura, S. [Hiroshima Univ. (Japan). School of Medicine

    2000-09-01

    We measured the apparent diffusion coefficient (ADC), using diffusion-weighted imaging (DWI) and signal intensity on T2-weighted MRI in the cerebral white matter of patients with progressive supranuclear palsy (PSP) and age-matched normal subjects. In PSP, ADC in the prefrontal and precentral white matter was significantly higher than in controls. There was no significant difference in signal intensity on T2-weighted images. The ADC did correlate with signal intensity. The distribution of the elevation of ADC may be the consequence of underlying pathological changes, such as neurofibrillary tangles or glial fibrillary tangles in the cortex. Our findings suggest that ADC measurement might be useful for demonstrating subtle neuropathological changes. (orig.)

  11. Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy.

    Directory of Open Access Journals (Sweden)

    Katherine J Kopeikina

    Full Text Available Neurofibrillary tangles (NFTs of tau are one of the defining hallmarks of Alzheimer's disease (AD, and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.

  12. Inhomogeneous distribution of Alzheimer pathology along the isocortical relief. Are cortical convolutions an Achilles heel of evolution?

    Science.gov (United States)

    Arendt, Thomas; Morawski, Markus; Gärtner, Ulrich; Fröhlich, Nadine; Schulze, Falko; Wohmann, Nils; Jäger, Carsten; Eisenlöffel, Christian; Gertz, Hermann-Josef; Mueller, Wolf; Brauer, Kurt

    2017-09-01

    Alzheimer's disease (AD) is neuropathologically characterized by neuritic plaques and neurofibrillary tangles. Progression of both plaques and tangles throughout the brain follows a hierarchical distribution which is defined by intrinsic cytoarchitectonic features and extrinsic connectivity patterns. What has less well been studied is how cortical convolutions influence the distribution of AD pathology. Here, the distribution of both plaques and tangles within subsulcal gyral components (fundi) to components forming their top regions at the subarachnoidal brain surface (crowns) by stereological methods in seven different cortical areas was systematically compared. Further, principle differences in cytoarchitectonic organization of cortical crowns and fundi that might provide the background for regionally selective vulnerability were attempted to identify. It was shown that both plaques and tangles were more prominent in sulcal fundi than gyri crowns. The differential distribution of pathology along convolutions corresponds to subgyral differences in the vascular network, GFAP-positive astrocytes and intracortical and subcortical connectivity. While the precise mechanisms accounting for these differences remain open, the presence of systematic inhomogeneities in the distribution of AD pathology along cortical convolutions indicates that the phylogenetic shaping of the cortex is associated with features that render the human brain vulnerable to AD pathology. © 2016 International Society of Neuropathology.

  13. The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

    Science.gov (United States)

    Merino-Serrais, Paula; Benavides-Piccione, Ruth; Blazquez-Llorca, Lidia; Kastanauskaite, Asta; Rábano, Alberto; Avila, Jesús

    2013-01-01

    The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer’s disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer’s disease is likely to depend on the relative number of neurons that have well developed tangles. PMID:23715095

  14. Crescimento e produção de manjericão em sistema hidropônico NFT sob salinidade

    Directory of Open Access Journals (Sweden)

    Maria A. A. Bione

    2014-12-01

    Full Text Available No semiárido brasileiro a falta de água de boa qualidade tem justificado o desenvolvimento de pesquisas científicas no aproveitamento de águas salobras. No presente trabalho avaliaram-se os efeitos de águas salobras em relação ao crescimento e à produção de plantas de manjericão em hidroponia, de outubro a novembro de 2012. Os tratamentos consistiram de quatro níveis de salinidade da água (1,45; 3,80; 6,08 e 8,48 dS m-1 obtidos pela adição de NaCl à água doce local, de um tratamento controle com essa água doce (0,29 dS m-1 e de um rejeito de osmose reversa (8,39 dS m-1 de um município do semiárido. Foram usadas 36 parcelas experimentais aleatorizadas em seis blocos. Os dados foram analisados mediante análise de variância e de regressão. Houve redução linear da produção de massa de matéria fresca e seca da parte aérea (MFPA e MSPA, com o aumento da salinidade, de 7,86 e 6,76% por acréscimo unitário na condutividade elétrica da água (dS m-1, respectivamente; não ocorreu diferença entre águas isosmóticas de NaCl e rejeito de dessalinização em referência à produção de MFPA. A altura de planta e a taxa de crescimento não indicaram a influência da salinidade no manjericão. As águas salobras não produziram sintomas depreciativos nas plantas.

  15. Tangled ruptures: discursive changes in Danish psychiatric nursing 1965-75

    DEFF Research Database (Denmark)

    Buus, N

    2001-01-01

    Psychiatric nursing and psychiatric nurses have been referred to in various ways over the course of history. These articulations reflect and constitute the ways in which nursing is comprehended during specific periods. A rupture in these descriptions and conceptions of Danish psychiatric nursing...... over the period 1965--75 is identified using a discourse analytical framework, inspired primarily by Foucault. This rupture influenced all aspects of psychiatric nursing: the perception of the psychiatric patient, the expertise and knowledge of the nurse and the care given by the nurse. The study...

  16. Tangled roots: Kalenda and other neo-African dances in the circum-Caribbean

    Directory of Open Access Journals (Sweden)

    Julian Gerstin

    2004-01-01

    Full Text Available Investigates descriptions of Afro-Caribbean dances in early chronicles and historical material. Author focuses on choreography, as well as on musical instruments and their use. He pays special attention to descriptions of the Martinican kalenda dance. He discusses descriptions from the 18th c. of black Caribbean dance in French and other colonies, by priests and others, of the kalenda as a couple dance within a ring, and descriptions of other widespread early dances in the Caribbean, such as chica. Author notes that in these early descriptions the authors focus obsessively on eroticism, thus simplifying and exaggerating the dances as sexual, and ignoring their variety. Further, he analyses early chronicles on other widespread dances in the circum-Caribbean, such as stick-fighting dances, bamboula, djouba, and belair, comparing with present-day Caribbean dances, and on "challenge dancing" involving a dance soloist "challenged" by a lead drummer, found, for instance, in kalenda and rumba. In addition, the author focuses on the dances' musical accompaniment by drums, and the drum types and methods, specifically transverse drumming and drumming with sticks on the side of the drum, found today in kalenda, and other Caribbean styles. He points at the inaccuracy of some chronicles, mixing up dance names, and recurring superficiality and stereotypes. He nonetheless concludes from them that slaves from the Congo/Angola region probably played a crucial role in forming these early dance styles, and that their spread was connected with French colonialism and slavery and migrations from (once French colonies. He describes probable Congolese/Angolan influences, such as pelvic isolation, challenge dances, couple dancing within a circle, and transverse drumming, but indicates that these are over time combined with other African and other influences.

  17. Inhomogeneous vortex tangles in counterflow superfluid turbulence: flow in convergent channels

    Directory of Open Access Journals (Sweden)

    Saluto Lidia

    2016-06-01

    Full Text Available We investigate the evolution equation for the average vortex length per unit volume L of superfluid turbulence in inhomogeneous flows. Inhomogeneities in line density L andincounterflowvelocity V may contribute to vortex diffusion, vortex formation and vortex destruction. We explore two different families of contributions: those arising from asecondorder expansionofthe Vinenequationitself, andthose whichare notrelated to the original Vinen equation but must be stated by adding to it second-order terms obtained from dimensional analysis or other physical arguments.

  18. Sensitive Judges – How to Resolve the Tangle of Legal Decision-Making and Emotion?

    NARCIS (Netherlands)

    Hamer, Jurriën

    2012-01-01

    According to traditional legal thought, emotions should have no influence on legal decision-making. The general assumption is that emotions interfere with clear rational thinking, and cause decisions to be biased and imbalanced. However, in modern philosophical thought, a different thesis has been

  19. "Mississippi Trial, 1955": Tangling with Text through Reading, Discussion, and Writing

    Science.gov (United States)

    Grierson, Sirpa; Thursby, Jacqueline S.; Dean, Deborah; Crowe, Chris

    2007-01-01

    The authors proffer practical critical-reading strategies for teaching "Mississippi Trial, 1955" to increase students' vocabulary, comprehension, and background knowledge of historical eras. They use nonfiction, a PBS documentary, the Web, folklore, and picture books among other tools for inciting thoughtful discussion and writing.

  20. T helper 17 cells and Regulatory T cells in Pulmonary Sarcoidosis : It takes two to tangle

    NARCIS (Netherlands)

    C.E. Broos (Caroline)

    2017-01-01

    markdownabstractSarcoidosis is an intriguingly complex immunological disorder. It is characterized by the formation of non-necrotizing granulomas that are most commonly found in the mediastinal lymph nodes and lungs of patients. Gaps in knowledge on sarcoidosis disease etiology and determinants of

  1. Tangled Up in Knots: Structures of Inactivated Forms of E. coli Class Ia Ribonucleotide Reductase

    Energy Technology Data Exchange (ETDEWEB)

    Zimanyi, Christina M.; Ando, Nozomi; Brignole, Edward J.; Asturias, Francisco J.; Stubbe, JoAnne; Drennan, Catherine L. (MIT); (Scripps)

    2012-10-23

    Ribonucleotide reductases (RNRs) provide the precursors for DNA biosynthesis and repair and are successful targets for anticancer drugs such as clofarabine and gemcitabine. Recently, we reported that dATP inhibits E. coli class Ia RNR by driving formation of RNR subunits into {alpha}{sub 4}{beta}{sub 4} rings. Here, we present the first X-ray structure of a gemcitabine-inhibited E. coli RNR and show that the previously described {alpha}{sub 4}{beta}{sub 4} rings can interlock to form an unprecedented ({alpha}{sub 4}{beta}{sub 4}){sub 2} megacomplex. This complex is also seen in a higher-resolution dATP-inhibited RNR structure presented here, which employs a distinct crystal lattice from that observed in the gemcitabine-inhibited case. With few reported examples of protein catenanes, we use data from small-angle X-ray scattering and electron microscopy to both understand the solution conditions that contribute to concatenation in RNRs as well as present a mechanism for the formation of these unusual structures.

  2. Navigating the patent landscapes for nanotechnology: English gardens or tangled grounds?

    Science.gov (United States)

    Sylvester, Douglas J; Bowman, Diana M

    2011-01-01

    The patent landscape, like a garden, can tell you much about its designers and users: their motivations, biases, and general interests. While both patent landscapes and gardens may appear to the casual observer as refined and ordered, an in-depth exploration of the terrain is likely to reveal unforeseen challenges including, for example, alien species, thickets, and trolls. As this chapter illustrates, patent landscapes are dynamic and have been forced to continually evolve in response to technological innovation. While emerging technologies such as biotechnology and information communication technology have challenged the traditional patent landscape, the overarching framework and design have largely remained intact. But will this always be the case? The aim of this chapter is to highlight how nanotechnology is challenging the existing structures and underlying foundation of the patent landscape and the implications thereof for the technology, industry, and public more generally. The chapter concludes by asking the question whether the current patent landscape will be able to withstand the ubiquitous nature of the technology, or whether nanotechnology will be a catalyst for governments and policy makers for overhauling the current landscape design.

  3. Pedagogy Meets Digital Media: A Tangle of Teachers, Strategies, and Tactics

    Science.gov (United States)

    Rust, Julie

    2017-01-01

    Although increasingly encouraged to incorporate digital media into classrooms to prepare students for engaged participation in a digital world, teachers are often taken by surprise when paradigm clashes arise between traditional school expectations and the affordances of these new spaces. Through data gathered from ethnographic methodologies…

  4. Progression from chronic atrophic gastritis to gastric cancer; tangle, toggle, tackle with Korea red ginseng.

    Science.gov (United States)

    Kim, Yoon Jae; Chung, Jun Won; Lee, So Jung; Choi, Ki Seok; Kim, Ju Hyun; Hahm, Ki Baik

    2010-05-01

    Key molecular players that link inflammation to carcinogenesis are prostaglandins, cytokines, nuclear factor-kappaB (NF-kappaB), chemokines, angiogenic growth factors, and free radicals, all of which lead to increased mutations and altered functions of important enzymes and proteins, for example, activation of oncogenic products and/or inhibition of tumor suppressor proteins, in inflamed tissues, thus contributing to multi-stage carcinogenesis process. Interpreted reversely, the identification of the molecular mechanisms by which chronic inflammation increases cancer risk or optimal intervention of targeted drugs or agents during the inflammation-associated carcinogenic process could be a necessary basis for developing new strategy of cancer prevention at many sites. In this review, we discuss the possibilities for cancer prevention by controlling inflammation process in Helicobacter pylori (H. pylori)-associated inflamed stomach with Korea red ginseng. Korea red ginseng is a good example of a natural herb that has ubiquitous properties that are conductive to stop inflammatory carcinogenesis that is un wanted outcome of H. pylori infection, rendering rejuvenation of chronic atrophic gastritis.

  5. Tangled history of the European uses of Sphagnum moss and sphagnol.

    Science.gov (United States)

    Drobnik, Jacek; Stebel, Adam

    2017-09-14

    Sphagnum mosses and peat could have been utilized as wound dressings for centuries, however reliable data on this subject are ambiguous; sometimes even no distinction between peat moss (Sphagnum spp.) and peat is made or these terms become confused. The first scientific account on surgical use of peat comes from 1882: a peat digger who successfully, by himself and in the way unknown to the then medicine, cured an open fracture of his forearm with peat. The peat, and very soon the peat moss itself (which is the major constituent of peat) drew attention of the 19th-century surgeons. We search for reliable information on: (1) inspirations for Sphagnum usage for medical purposes and its beginnings in the 19th century, (2) substances or products named sphagnol and their connections with (1); (3) on the origin of this name, (4) and on the occurrence of this name in medical sources. We have identified and studied published sources on the uses of peat-based and Sphagnum-based preparations and products of any processing level (including herbal stock, distillate, isolated pure or impure active principle, or a mixture of such) in surgery, pharmacy or cosmetics. A special attention was paid to the name sphagnol, which appeared many a time, in more than one context since 1899. Source publications were critically analysed from the taxonomical, pharmacognostical and ethnopharmacological points of view. Gathered data were cross-checked with the modern knowledge of the biologically active principles of Sphagnum and the prospects of their medical use. The application of peat in surgery started 1882. The use of peat moss as dressings was developed in the 1880's. It returned to surgical practice during WW1. The name sphagnol has two meanings: (1) A chemical substance isolated from the cell walls of Sphagnum mosses in 1899. A post-1950 research showed it to be a mixture of phenols dominated by sphagnum acid. (2) A product of dry distillation of peat contains solid and liquid fractions and was applied in skin diseases due to antiseptic properties. It was added to ointments and medicated soaps manufactured up to the late 1960's. Today none of these two sphagnols is in use. Surgical application of peat had an ethnopharmacological origin: a case of wound treatment with peat as a remedy rather than a dressing (1880, published 1882) shortly shifted the surgeons' attention to peat moss as an absorptive dressing. The 1880's tests of antiseptic properties of peat and peat moss failed, the sterilization methods overrode the physiological effects of Sphagnum dressings. Sphagnan, a polysaccharide from Sphagnum cell walls, discovered 1983, inhibits microbial growth, tans the collagen and removes ammonia from microbial environments. Portions of raw peat could be sterile. The isolation of sphagnol (1899) from Sphagnum cell walls was not inspired by old surgery. Main component of sphagnol, the sphagnic acid, was used clinically during WW2, but was proved a weak antimicrobial agent. A homonymous name sphagnol appeared independently for a product of dry distillation of peat, introduced commercially probably about 1899, too, which gave rise to confusions: a) the commercial, "distilled" sphagnol was not the crystalline principle of Sphagnum cell walls. 2) the "distilled" sphagnol was hardly defined technologically or pharmacologically, never standardized in terms of the substrate (a variety of peat rather than Sphagnum herb) and the production process. This sphagnol, resembling pitch or tar, was an additive to medicated soaps and ointments for skin treatment and care. It must have been a low-scale product although advertised worldwide. Neither sphagnum acid nor sphagnan are used medicinally today. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  6. Untangling the Tangled Webs We Weave: A Team Approach to Cyberspace.

    Science.gov (United States)

    Broidy, Ellen; And Others

    Working in a cooperative team environment across libraries and job classifications, librarians and support staff at the University of California at Irvine (UCI) have mounted several successful web projects, including two versions of the Libraries' home page, a virtual reference collection, and Science Library "ANTswer Machine." UCI's…

  7. The Tangled Web: Investigating Academics' Views of Plagiarism at the University of Cape Town

    Science.gov (United States)

    de Jager, Karin; Brown, Cheryl

    2010-01-01

    This article considers the problematic question of student plagiarism, its causes and manifestations, and how it is addressed in academic environments. A literature survey was conducted to establish how higher education institutions approach these issues, and a twofold investigation was conducted at the University of Cape Town. Data was gathered…

  8. The Tangled Web of Agricultural Insurance: Evaluating the Impacts of Government Policy

    OpenAIRE

    Jason Pearcy; Vincent Smith

    2015-01-01

    This paper examines the effects of changes in major elements of the U.S. federal crop insurance program on the structure of the agricultural insurance industry. We model the interactions between farmers, insurance agents and insurance companies. Two symmetric equilibria are determined: one with competitive insurance companies and one where insurance companies form a collusive monopsony. We evaluate how marginal changes in government policy (changes in the premium subsidy rate, A&O subsidy rat...

  9. Tangled roots: Kalenda and other neo-African dances in the circum-Caribbean

    OpenAIRE

    Julian Gerstin

    2004-01-01

    Investigates descriptions of Afro-Caribbean dances in early chronicles and historical material. Author focuses on choreography, as well as on musical instruments and their use. He pays special attention to descriptions of the Martinican kalenda dance. He discusses descriptions from the 18th c. of black Caribbean dance in French and other colonies, by priests and others, of the kalenda as a couple dance within a ring, and descriptions of other widespread early dances in the Caribbean, such as ...

  10. Tangled up in Blue: Boosting Mental Health Services at Community Colleges

    Science.gov (United States)

    Finkel, Ed

    2016-01-01

    In a recent survey of 4,000 community college students, half reported experiencing a mental health condition. American College Counseling Association's (ACCA) fifth annual survey of personal and mental health counseling at community colleges provides some data from 159 professionals at two-year colleges in 41 states and Puerto Rico. Among the…

  11. Net-based information on varicose vein treatments: a tangled web.

    Science.gov (United States)

    Ching, Thida; Roake, Justin A; Lewis, David R

    2010-09-24

    30-40% of individuals will be affected by varicose veins during their lifetime. Many will contemplate treatment and will access the (Inter)net for information. The aim of this study is to determine whether New Zealand-based websites are an accurate source of information for the public. Inclusion criteria were New Zealand based websites that contained information on varicose vein treatments. These websites were identified using the search-engines Google and Yahoo. The first 60 websites from each were evaluated and subdivided into 4 groups based on web-site ownership: (1) Vein clinic/hospital; (2) Appearance medicine; (3) Online stores; (4) Health editorials; and (5) Medical resources. 46 of the 120 websites satisfied the inclusion criteria. 18 websites (39%) explained what varicose veins were. Information about treatment options was most comprehensive in the "Vein clinic/hospital" group. The "Appearance medicine" group mostly contained information on outpatient interventional therapies. "Health editorial" sites had lifestyle modification options. All the online herbal/health stores mentioned herbal treatment options. Few websites fully informed patients about treatment options while some simply advertised non-evidence based treatments. This study suggests that the Internet is not a reliable source of information and does not accurately inform patients about varicose veins and the treatment options.

  12. Modeling non-hereditary mechanisms of Alzheimer disease during apoptosis in yeast.

    Science.gov (United States)

    Braun, Ralf J; Sommer, Cornelia; Leibiger, Christine; Gentier, Romina J; Dumit, Verónica I; Paduch, Katrin; Eisenberg, Tobias; Habernig, Lukas; Trausinger, Gert; Magnes, Christoph; Pieber, Thomas; Sinner, Frank; Dengjel, Jörn; Leeuwen, Fred W V; Kroemer, Guido; Madeo, Frank

    2015-03-20

    Impaired protein degradation and mitochondrial dysfunction are believed to contribute to neurodegenerative disorders, including Alzheimer disease (AD). In patients suffering from non-hereditary AD, UBB +1 , the frameshift variant of ubiquitin B, accumulated in neurons affected by neurofibrillary tangles, which is a pathological hallmark. We established a yeast model expressing high levels of UBB +1 , and could demonstrate that UBB +1 interfered with both the ubiquitin-proteasome system (UPS) and mitochondrial function. More precisely, UBB +1 promoted the mitochondrion-localized production of the basic amino acids arginine, ornithine, and lysine, which we identified as the decisive toxic event culminating in apoptosis. Inducing the UPS activity at mitochondria prevented the lethal basic amino acid accumulation and avoided UBB +1 -triggered cell loss. The arginine/ornithine metabolism is altered in brains of AD patients, and VMS1, the mitochondrion-specific UPS component, co-existed with UBB +1 in neurofibrillary tangles. Therefore, our data suggest that aberrant basic amino acid synthesis is a crucial link between UPS dysfunction and mitochondrial damage during AD progression.

  13. Alzheimer disease pathology in subjects without dementia in 2 studies of aging: the Nun Study and the Adult Changes in Thought Study.

    Science.gov (United States)

    SantaCruz, Karen S; Sonnen, Joshua A; Pezhouh, Maryam Kherad; Desrosiers, Mark F; Nelson, Peter T; Tyas, Suzanne L

    2011-10-01

    Individuals with antemortem preservation of cognition who show autopsy evidence of at least moderate Alzheimer disease (AD) pathology suggest the possibility of brain reserve, that is, functional resistance to structural brain damage. This reserve would, however, only be relevant if the pathologic markers correlate well with dementia. Using data from the Nun Study (n = 498) and the Adult Changes in Thought (ACT) Study (n = 323), we show that Braak staging correlates strongly with dementia status. Moreover, participants with severe(Braak stage V-VI) AD pathology who remained not demented represent only 12% (Nun Study) and 8% (ACT study) of nondemented subjects. Comparison of these subjects to those who were demented revealed that the former group was often significantly memory-impaired despite not being classified as demented. Most of these nondemented participants showed only stage V neurofibrillary pathology and frontal tangle counts that were slightly lower than a comparable (Braak stage V) dementia group. In summary, these data indicate that, in individuals with AD-type pathology who do not meet criteria for dementia, neocortical neurofibrillary tangles are somewhat reduced and incipient cognitive decline is present. Our data provide a foundation for helping to define additional factors that may impair, or be protective of, cognition in older adults.

  14. N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer's disease.

    Science.gov (United States)

    Gironès, Xavier; Guimerà, Arantxa; Cruz-Sánchez, Celia-Z; Ortega, Arantxa; Sasaki, Noboyuki; Makita, Zenji; Lafuente, José Vivente; Kalaria, Raj; Cruz-Sánchez, Félix F

    2004-05-15

    Oxidative stress has been implicated in the pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM). N epsilon-carboxymethyllysine (CML) is an advanced glycation end product (AGE) recently found to be associated with oxidative stress mechanisms. Using immunocytochemical methods we examined the distribution of CML in brain tissue from AD and DM subjects and aging controls. CML reactivity was present in the cytoplasm of neurons, but there were marked differences in the intensity of expression, number of cells, and topographical distribution. CML expression was higher in hippocampus than in frontal and temporal cortex. In the hippocampus, neuronal and, to an extent, glial expression was more marked in CA3 and CA4 than in CA1 and CA2. In AD, CML was found to be coexpressed with tau protein, showing the similar neurofibrillary tangle shape, as well as in neuritic plaques but not in the core of amyloid plaques. We noted an increasing degree of CML expression such that the highest reactivity was evident in those with both AD and DM, followed by AD, DM, and aging controls. There was an inverse relationship between Braak staging and topography of CML expression. Although DM cases did not show Abeta deposition or neurofibrillary tangles, these findings suggest increased CML expression is not limited to AD. Nonetheless, high CML expression in AD with coexistent DM suggests there are additive effects compared with AD alone. It is plausible that the microangiopathy also associated with DM could worsen AD pathogenesis.

  15. Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy following Repetitive Head Injury

    Science.gov (United States)

    McKee, Ann C.; Cantu, Robert C.; Nowinski, Christopher J.; Hedley-Whyte, E. Tessa; Gavett, Brandon E.; Budson, Andrew E.; Santini, Veronica E.; Lee, Hyo-Soon; Kubilus, Caroline A.; Stern, Robert A.

    2009-01-01

    Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed “dementia pugilistica” and more recently, chronic traumatic encephalopathy (CTE). We review the 47 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professional athletes: one football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, Parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular, patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. CTE is a neuropathologically distinct, slowly progressive tauopathy with a clear environmental etiology. PMID:19535999

  16. Chronic traumatic encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal practice questions.

    Science.gov (United States)

    Omalu, Bennet I; Hamilton, Ronald L; Kamboh, M Ilyas; DeKosky, Steven T; Bailes, Julian

    2010-01-01

    We present a case of chronic traumatic encephalopathy (CTE) in a retired National Football League (NFL) Player with autopsy findings, apolipoprotein E genotype, and brain tissue evidence of chronic brain damage. This 44-year-old retired NFL player manifested a premortem history of cognitive and neuropsychiatric impairment, which included in part, chronic depression, suicide attempts, insomnia, paranoia, and impaired memory before he finally committed suicide. A full autopsy was performed with Polymerase Chain Reaction-based analyses of his blood to determine the apolipoprotein genotype. Histochemical and immunohistochemical analyses were performed on topographical gross sections of the brain. Autopsy confirmed a fatal gunshot wound of the head. The apolipoprotein E genotype was E3/E3 and the brain tissue revealed diffuse cerebral taupathy (Neurofibrillary Tangles and Neuritic Threads). This will be the third case of CTE in a national football player, which has been reported in the medical literature. Omalu et al., reported the first two cases in 2005 and 2006. This case series manifested similar premortem history of neuropsychiatric impairment with autopsy evidence of cerebral taupathy without any neuritic amyloidopathy. For a definitive diagnosis of CTE to be made, and for medicolegal purposes, a full autopsy must be performed with histochemical and immunohistochemical analyses of the brain to identify the presence of Neurofibrillary Tangles (NFTs) and Neuritic Threads (NTs). Further longitudinal prospective studies are required to confirm the common denominators and epidemiology of CTE in professional American football players, which have been identified by this case series.

  17. Early-onset familial lewy body dementia with extensive tauopathy: a clinical, genetic, and neuropathological study.

    Science.gov (United States)

    Clarimón, Jordi; Molina-Porcel, Laura; Gómez-Isla, Teresa; Blesa, Rafael; Guardia-Laguarta, Cristina; González-Neira, Anna; Estorch, Montserrat; Ma Grau, Josep; Barraquer, Lluís; Roig, Carles; Ferrer, Isidre; Lleó, Alberto

    2009-01-01

    We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient disclosed unusual features characterized by diffuse Lewy body disease and generalized neurofibrillary tangle pathology but with no amyloid deposits in any region. Moreover, Lewy body pathology colocalized with neurofibrillary tangles in most affected neurons. Mutation screening that included all coding exons of presenilin 1 (PSEN1), presenilin 2 (PSEN2), alpha-synuclein (SNCA), beta-synuclein (SNCB), microtubule-associated protein tau (MAPT), leucine-rich repeat kinase 2 (LRRK2), glucocerebrosidase (GBA), and exons 16 and 17 of the amyloid precursor protein (APP) genes did not identify any mutation. Genome-wide single nucleotide polymorphism was performed in 4 family members and ruled out any pathogenic duplication or deletion in the entire genome. In summary, we report a unique family with pathologically confirmed early-onset dementia with Lewy bodies with widespread tau and alpha-synuclein deposition. The absence of mutations in genes known to cause Lewy body disease suggests that a novel locus or loci are implicated in this neurodegenerative disease.

  18. Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains.

    Science.gov (United States)

    Lüth, Hans-Joachim; Ogunlade, Vera; Kuhla, Björn; Kientsch-Engel, Rosemarie; Stahl, Peter; Webster, Julie; Arendt, Thomas; Münch, Gerald

    2005-02-01

    In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.

  19. Mass spectrometry assessment of ubiquitin carboxyl-terminal hydrolase L1 partitioning between soluble and particulate brain homogenate fractions.

    Science.gov (United States)

    Chen, Junjun; Huang, Richard Y-C; Turko, Illarion V

    2013-06-18

    Partitioning of specific proteins between soluble and insoluble forms because of aggregation, membrane attachment, and (or) association with senile plaques and neurofibrillary tangles is a major feature of several neurodegenerative disorders, including Alzheimer's disease (AD). Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is an example of a neuron-specific protein which displays two different dimerization-dependent catalytic activities and can be farnesylated for membrane attachment, oxidized, and truncated. Decreased levels of soluble UCH-L1 are inversely proportional to the number of neurofibrillary tangles. Further assessment of a link between UCH-L1 function and the pathogenesis of AD requires an analytical method to separately quantify different UCH-L1 forms. In the present study, we have developed a multiple reaction monitoring (MRM) assay to measure UCH-L1 in the high-speed supernatant and pellet of frontal cortex homogenate. The well-characterized (15)N-labeled quantification concatamer (QconCAT) carrying prototypic tryptic peptides of UCH-L1 was used as an internal standard. The composed protocol of frontal cortex processing includes solubilization and reduction/alkylation of proteins in the presence of 1% sodium dodecyl sulfate (SDS) and following with desalting/delipidation of the sample by chloroform/methanol precipitation with extra water washing of the protein pellet. The measurements were performed for frontal cortex samples from control and severe AD donors. The proposed workflow can be recommended for quantification of partitioning of other proteins of interest.

  20. Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease.

    Science.gov (United States)

    Bonda, David J; Mailankot, Maneesh; Stone, Jeremy G; Garrett, Matthew R; Staniszewska, Magdalena; Castellani, Rudy J; Siedlak, Sandra L; Zhu, Xiongwei; Lee, Hyoung-gon; Perry, George; Nagaraj, Ram H; Smith, Mark A

    2010-01-01

    Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxyanthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-beta accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimer's diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's disease.

  1. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury.

    Science.gov (United States)

    McKee, Ann C; Cantu, Robert C; Nowinski, Christopher J; Hedley-Whyte, E Tessa; Gavett, Brandon E; Budson, Andrew E; Santini, Veronica E; Lee, Hyo-Soon; Kubilus, Caroline A; Stern, Robert A

    2009-07-01

    Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.

  2. Inhibition of Protein Phosphatase-2A (PP2A) by I1PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats.

    Science.gov (United States)

    Wang, Xiaochuan; Blanchard, Julie; Tung, Yunn Chyn; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-01-01

    Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I(1)(PP2A)) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I(1)(PP2A) can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I(1)(PP2A). In the adult AAV1-I(1)(PP2A) rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I(1)(PP2A) animals, suggesting that I(1)(PP2A) can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I(1)(PP2A) induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I(1)(PP2A) can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.

  3. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis.

    Science.gov (United States)

    Bloom, George S

    2014-04-01

    The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive

  4. Amyloid beta 1-42 and phoshorylated tau threonin 231 in brains of aged cynomolgus monkeys (Macaca fascicularis

    Directory of Open Access Journals (Sweden)

    Huda Shalahudin Darusman

    2014-11-01

    Full Text Available Pathological hallmarks indicative of Alzheimer’s disease, which are the plaques of Amyloid Beta 1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of the study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of Alzheimer’s disease, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of Amyloid beta 1-42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of Alzheimer’s disease, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of Amyloid Beta 1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of Alzheimer’s disease. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease.

  5. Neuronal COX-2 expression and phosphorylation of pRb precede p38 MAPK activation and neurofibrillary changes in AD temporal cortex

    NARCIS (Netherlands)

    Hoozemans, Jeroen J. M.; Veerhuis, Robert; Rozemuller, Annemieke J. M.; Arendt, Thomas; Eikelenboom, Piet

    2004-01-01

    In Alzheimer's disease (AD) brain, increased levels of cyclooxygenase-2 (COX-2), cell cycle markers, and p38 MAP kinase (MAPK) can be detected in neuronal cells. Besides mediating COX-2 expression, p38 MAPK is suggested to mediate cell cycle progression through phosphorylation of the retinoblastoma

  6. Examination of the Clinicopathologic Continuum of Alzheimer Disease in the Autopsy Cohort of the National Alzheimer Coordinating Center

    Science.gov (United States)

    Serrano-Pozo, Alberto; Qian, Jing; Monsell, Sarah E.; Frosch, Matthew P.; Betensky, Rebecca A.; Hyman, Bradley T.

    2014-01-01

    To test the hypothesis that Alzheimer disease (AD) is a clinical and pathologic continuum between normal aging and end-stage dementia, we selected a convenience sample of subjects from the National Alzheimer Coordinating Center 2005 to 2012 autopsy cohort (n = 2,083) with the last clinical evaluation within 2 years before autopsy and no other primary neuropathologic diagnosis. Demographic and neuropathologic characteristics were correlated with the Clinical Dementia Rating–Sum of Boxes in the 835 subjects meeting these criteria. Both neuritic plaques and neurofibrillary tangles independently predicted Clinical Dementia Rating–Sum of Boxes. Severe small-vessel disease, severe amyloid angiopathy, and hippocampal sclerosis were also independently associated with the degree of cognitive impairment. By contrast, education was a strong independent protective factor against cognitive deficits. The cause of mild to moderate dementia remained uncertain in 14% of the patients. Inverse probability weighting suggests the generalizability of these results to nonautopsied cohorts. These data indicate that plaques and tangles independently contribute to cognitive impairment, that concurrent vascular disease strongly correlates with cognitive dysfunction even in a sample selected to represent the AD pathologic continuum, and that education further modifies clinical expression. Thus, multiple concomitant etiologies of brain damage and premorbid characteristics contribute to the uncertainty of AD clinicopathologic correlations based only on tangles and plaques. PMID:24226270

  7. Improvements in Alzheimer's disease diagnosis using principle components analysis (PCA) in combination with Raman spectroscopy

    Science.gov (United States)

    Archer, John K. J.; Sudworth, Caroline D.; Williams, Rachel; How, Thien; Stone, Nicholas; Mann, David; Black, Richard A.

    2007-07-01

    The significant achievements of medical science over the last century are evident in the increasing age of the global population, however this now brings new problems, the most prominent being the growth in the number of people suffering from dementia. Over half the people with dementia in the UK are sufferers of Alzheimer's disease, a condition in which intraneuronal neurofibrillary tangles and extraneuronal senile tangles take over neurons prompting their death. A definitive diagnosis is still only currently available post-mortem, whilst current symptom based processes of elimination are far from perfect, especially when the only treatments available are symptom inhibiting drugs. Principal component analysis (PCA) of the Raman spectra taken from brain tissue has proved to be a potential tool in the diagnosis. However, this work now has to be refined in order to progress to tissue less associated with the symptoms of Alzheimer's disease. The first step of this has already been taken in progressing from frontal tissue to occipital tissue point spectra taken at random positions from bulk tissue. Now we present initial work into acquiring Raman spectral maps from across a tissue area, in pursuit of identifying unique plaque and tangle spectra. These spectra are presented alongside synthetic β-Amyloid spectra, in a study of the role that the peptide plays in the biomarker spectra, and how this information can aid the PCA of bulk tissue, and point towards a Raman spectroscopic test on less sensitive tissue, such as blood.

  8. Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study.

    Science.gov (United States)

    Wharton, Stephen B; Minett, Thais; Drew, David; Forster, Gillian; Matthews, Fiona; Brayne, Carol; Ince, Paul G

    2016-02-08

    Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer's disease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, but abundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by the BrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined the relationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas. Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p pathology.

  9. Diabetes Mellitus Induces Alzheimer’s Disease Pathology: Histopathological Evidence from Animal Models

    Directory of Open Access Journals (Sweden)

    Nobuyuki Kimura

    2016-04-01

    Full Text Available Alzheimer’s disease (AD is the major causative disease of dementia and is characterized pathologically by the accumulation of senile plaques (SPs and neurofibrillary tangles (NFTs in the brain. Although genetic studies show that β-amyloid protein (Aβ, the major component of SPs, is the key factor underlying AD pathogenesis, it remains unclear why advanced age often leads to AD. Interestingly, several epidemiological and clinical studies show that type II diabetes mellitus (DM patients are more likely to exhibit increased susceptibility to AD. Moreover, growing evidence suggests that there are several connections between the neuropathology that underlies AD and DM, and there is evidence that the experimental induction of DM can cause cognitive dysfunction, even in rodent animal models. This mini-review summarizes histopathological evidence that DM induces AD pathology in animal models and discusses the possibility that aberrant insulin signaling is a key factor in the induction of AD pathology.

  10. Epidemiology of Alzheimer Disease

    Science.gov (United States)

    Mayeux, Richard; Stern, Yaakov

    2012-01-01

    The global prevalence of dementia has been estimated to be as high as 24 million, and is predicted to double every 20 years until at least 2040. As the population worldwide continues to age, the number of individuals at risk will also increase, particularly among the very old. Alzheimer disease is the leading cause of dementia beginning with impaired memory. The neuropathological hallmarks of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in brain that are frequently surrounded by dystrophic neurites and intraneuronal neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is likely to be the result of both genetic and environmental factors. In this review we discuss the prevalence and incidence rates, the established environmental risk factors, and the protective factors, and briefly review genetic variants predisposing to disease. PMID:22908189

  11. Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers.

    Science.gov (United States)

    Reitz, Christiane; Mayeux, Richard

    2014-04-15

    The global prevalence of dementia is as high as 24 million, and has been predicted to quadruple by the year 2050. In the US alone, Alzheimer disease (AD) - the most frequent cause of dementia characterized by a progressive decline in cognitive function in particular the memory domain - causes estimated health-care costs of $ 172 billion per year. Key neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques - often surrounded by dystrophic neurites - and intracellular neurofibrillary tangles. These pathological changes are frequently accompanied by reactive microgliosis and loss of neurons, white matter and synapses. The etiological mechanisms underlying these neuropathological changes remain unclear, but are probably caused by both environmental and genetic factors. In this review article, we provide an overview of the epidemiology of AD, review the biomarkers that may be used for risk assessment and in diagnosis, and give suggestions for future research. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

    Science.gov (United States)

    Kanatsu, Kunihiko; Tomita, Taisuke

    2017-01-01

    Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1 . In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2 . We review the recent findings related to the molecular mechanisms by which these genetic risk factors contribute to AD, and our perspectives regarding the etiology of AD for the development of therapeutic agents.

  13. Genetic aspects of Alzheimer disease.

    Science.gov (United States)

    Bird, Thomas D

    2008-04-01

    Alzheimer disease is the most common cause of dementia and represents a major public health problem. The neuropathologic findings of amyloid-beta plaques and tau containing neurofibrillary tangles represent important molecular clues to the underlying pathogenesis. Genetic factors are well recognized, but complicated. Three rare forms of autosomal-dominant early-onset familial Alzheimer disease have been identified and are associated with mutations in amyloid precursor protein, presenilin 1, and presenilin 2 genes. The more common late-onset form of Alzheimer disease is assumed to be polygenic/multifactorial. However, thus far the only clearly identified genetic risk factor for Alzheimer disease is Apo lipoprotein E. The epsilon4 allele of Apo lipoprotein E influences age at onset of Alzheimer disease, but is neither necessary nor sufficient for the disease. The search continues for the discovery of additional genetic influences.

  14. Genetic alterations of the BR12 Gene: familial British and Danish dementias

    DEFF Research Database (Denmark)

    Ghiso, J.; Rostagno, A.; Tomidokoro, Y.

    2006-01-01

    Classic arguments sustaining the importance of amyloid in the pathogenesis of dementia are usually centered on amyloid β (Aβ) and its role in neuronal loss characteristic of Alzheimer disease, the most common form of human cerebral amyloidosis. Two non-Aβ cerebral amyloidoses, familial British...... and Danish dementias, share many aspects of Alzheimer disease, including the presence of neurofibrillary tangles, parenchymal pre-amyloid and amyloid deposits, cerebral amyloid angiopathy, and a widespread inflammatory response. Both early-onset conditions are linked to specific mutations in the BRI2 gene......, causing the generation of longer-than-normal protein products and the release of 2 de novo created peptides ABri and ADan, the main components of amyloid fibrils in these inherited dementias. Although the molecular mechanisms and signal transduction pathways elicited by the amyloid deposits...

  15. Chronic traumatic encephalopathy: The unknown disease.

    Science.gov (United States)

    Martínez-Pérez, R; Paredes, I; Munarriz, P M; Paredes, B; Alén, J F

    2017-04-01

    Chronic traumatic encephalopathy is a neurodegenerative disease produced by accumulated minor traumatic brain injuries; no definitive premortem diagnosis and no treatments are available for chronic traumatic encephalopathy. Risk factors associated with chronic traumatic encephalopathy include playing contact sports, presence of the apolipoprotein E4, and old age. Although it shares certain histopathological findings with Alzheimer disease, chronic traumatic encephalopathy has a more specific presentation (hyperphosphorylated tau protein deposited as neurofibrillary tangles, associated with neuropil threads and sometimes with beta-amyloid plaques). Its clinical presentation is insidious; patients show mild cognitive and emotional symptoms before progressing to parkinsonian motor signs and finally dementia. Results from new experimental diagnostic tools are promising, but these tools are not yet available. The mainstay of managing this disease is prevention and early detection of its first symptoms. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  16. Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

    Directory of Open Access Journals (Sweden)

    Kevin A. Clayton

    2017-12-01

    Full Text Available Brain aging is central to late-onset Alzheimer's disease (LOAD, although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.

  17. Amnesia in Frontotemporal Dementia with Amyotrophic Lateral Sclerosis, Masquerading Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    A. Yamanami-Irioka

    2011-10-01

    Full Text Available A 68-year-old man with a clinical diagnosis of Alzheimer’s disease (AD later developed amyotrophic lateral sclerosis (ALS, which was confirmed at autopsy at age 72 years. Because neuronal loss and AD-type pathologies (Braak stage II for neurofibrillary tangles were scant, TDP-43-positive intracytoplasmic inclusions in hippocampal dentate granular cells and in neurons in the subiculum and amygdala, even though small in amount, may represent the earliest lesions of ALS-related dementia and could be the cause of dementia in this patient. Although the persistent elevation of creatine kinase from the onset could be a pointer to the presence of motor involvement, more accurate characterization of dementia, which may differentiate ALS-related dementia and AD, is necessary.

  18. The Complexity of Sporadic Alzheimer’s Disease Pathogenesis: The Role of RAGE as Therapeutic Target to Promote Neuroprotection by Inhibiting Neurovascular Dysfunction

    Directory of Open Access Journals (Sweden)

    Lorena Perrone

    2012-01-01

    Full Text Available Alzheimer's disease (AD is the most common cause of dementia. Amyloid plaques and neurofibrillary tangles are prominent pathological features of AD. Aging and age-dependent oxidative stress are the major nongenetic risk factors for AD. The beta-amyloid peptide (Aβ, the major component of plaques, and advanced glycation end products (AGEs are key activators of plaque-associated cellular dysfunction. Aβ and AGEs bind to the receptor for AGEs (RAGE, which transmits the signal from RAGE via redox-sensitive pathways to nuclear factor kappa-B (NF-κB. RAGE-mediated signaling is an important contributor to neurodegeneration in AD. We will summarize the current knowledge and ongoing studies on RAGE function in AD. We will also present evidence for a novel pathway induced by RAGE in AD, which leads to the expression of thioredoxin interacting protein (TXNIP, providing further evidence that pharmacological inhibition of RAGE will promote neuroprotection by blocking neurovascular dysfunction in AD.

  19. The Impact of Cholesterol, DHA, and Sphingolipids on Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Marcus O. W. Grimm

    2013-01-01

    Full Text Available Alzheimer’s disease (AD is a devastating neurodegenerative disorder currently affecting over 35 million people worldwide. Pathological hallmarks of AD are massive amyloidosis, extracellular senile plaques, and intracellular neurofibrillary tangles accompanied by an excessive loss of synapses. Major constituents of senile plaques are 40–42 amino acid long peptides termed β-amyloid (Aβ. Aβ is produced by sequential proteolytic processing of the amyloid precursor protein (APP. APP processing and Aβ production have been one of the central scopes in AD research in the past. In the last years, lipids and lipid-related issues are more frequently discussed to contribute to the AD pathogenesis. This review summarizes lipid alterations found in AD postmortem brains, AD transgenic mouse models, and the current understanding of how lipids influence the molecular mechanisms leading to AD and Aβ generation, focusing especially on cholesterol, docosahexaenoic acid (DHA, and sphingolipids/glycosphingolipids.

  20. In vivo functional brain mapping in a conditional mouse model of human tauopathy (tauP301L) reveals reduced neural activity in memory formation structures.

    Science.gov (United States)

    Perez, Pablo D; Hall, Gabrielle; Kimura, Tetsuya; Ren, Yan; Bailey, Rachel M; Lewis, Jada; Febo, Marcelo; Sahara, Naruhiko

    2013-02-04

    Tauopathies are characterized by intracellular deposition of the microtubule-associated protein tau as filamentous aggregates. The rTg4510 mouse conditionally expresses mutant human tau protein in various forebrain areas under the Tet-off expression system. Mice develop neurofibrillary tangles, with significant neuronal loss and cognitive deficits by 6 months of age. Previous behavioral and biochemical work has linked the expression and aggregates of mutant tau to functional impairments. The present work used manganese-enhanced magnetic resonance imaging (MEMRI) to investigate basal levels of brain activity in the rTg4510 and control mice. Our results show an unmistakable curtailment of neural activity in the amygdala and hippocampus, two regions known for their role in memory formation, but not the cortex, cerebellum, striatum and hypothalamus in tau expressing mice. Behavioral impairments associated with changes in activity in these areas may correspond to age progressive mutant tau(P301L)-induced neurodegeneration.

  1. Role of metal ions in the cognitive decline of Down syndrome

    Directory of Open Access Journals (Sweden)

    Nakisa eMalakooti

    2014-06-01

    Full Text Available Down syndrome (DS, caused by trisomy of whole or part of chromosome 21 is the most common mental impairment. All Down syndrome (DS individuals suffer from cognitive decline and develop Alzheimer’s disease (AD by the age of forty. The appearance of enlarged early endosomes, followed by Amyloid β peptide deposition, the appearance of tau-containing neurofibrillary tangles and basal forebrain cholinergic neuron (BFCN degeneration are the neuropathological characteristics of this disease. In this review we will examine the role of metal ion dyshomeostasis and the genes which may be involved in these processes, and relate these back to the manifestation of age-dependant cognitive decline in DS.

  2. Beta-Amyloid Deposition and Alzheimer's Type Changes Induced by Borrelia Spirochetes

    Energy Technology Data Exchange (ETDEWEB)

    Miklossy,J.; Kis, A.; Radenovic, A.; Miller, L.; Forro, L.; Martins, R.; Reiss, K.; Darbinian, N.; Darekar, P.; et al.

    2006-01-01

    The pathological hallmarks of Alzheimer's disease (AD) consist of {beta}-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of {beta}-amyloid presursor protein (A{beta}PP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.

  3. Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease.

    Science.gov (United States)

    He, Hongwen; Dong, Weiguo; Huang, Fang

    2010-09-01

    Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by the presence of senile plaques, neurofibrillary tangles and neuronal loss. Amyloid-β protein (Aβ) deposition plays a critical role in the development of AD. It is now generally accepted that massive neuronal death due to apoptosis is a common characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. Melatonin is a secretory product of the pineal gland; melatonin is a potent antioxidant and free radical scavenger and may play an important role in aging and AD. Melatonin decreases during aging and patients with AD have a more profound reduction of this indoleamine. Additionally, the antioxidant properties, the anti-amyloidogenic properties and anti-apoptotic properties of melatonin in AD models have been studied. In this article, we review the anti-amyloidogenic and anti-apoptotic role of melatonin in AD.

  4. A quantitative study of intracranial calcification in dementia of the Alzheimer type.

    Science.gov (United States)

    Friedland, R P; Luxenberg, J S; Koss, E

    1990-01-01

    Abnormalities in calcium homeostasis have been reported in Alzheimer's disease (AD) and in the neurofibrillary tangle disorders of amyotrophic lateral sclerosis and parkinsonism-dementia occurring in the Pacific. In order to more fully evaluate calcium physiology in AD, we analyzed the size of pineal and choroid plexus calcifications, using X-ray computed tomography, in 23 patients with probable AD and 18 healthy age-matched control subjects. The area occupied by calcification was measured from hard copies of the data by two independent observers who were blind to the diagnosis. There were no differences in the areas occupied by pineal or choroid plexus calcifications between the two groups. These data suggest that AD is not accompanied by alternations in intracranial calcium deposition in pineal gland or choroid plexus.

  5. Dissecting Endoplasmic Reticulum Unfolded Protein Response (UPRER in Managing Clandestine Modus Operandi of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Safikur Rahman

    2018-02-01

    Full Text Available Alzheimer’s disease (AD, a neurodegenerative disorder, is most common cause of dementia witnessed among aged people. The pathophysiology of AD develops as a consequence of neurofibrillary tangle formation which consists of hyperphosphorylated microtubule associated tau protein and senile plaques of amyloid-β (Aβ peptide in specific brain regions that result in synaptic loss and neuronal death. The feeble buffering capacity of endoplasmic reticulum (ER proteostasis in AD is evident through alteration in unfolded protein response (UPR, where UPR markers express invariably in AD patient’s brain samples. Aging weakens UPRER causing neuropathology and memory loss in AD. This review highlights molecular signatures of UPRER and its key molecular alliance that are affected in aging leading to the development of intriguing neuropathologies in AD. We present a summary of recent studies reporting usage of small molecules as inhibitors or activators of UPRER sensors/effectors in AD that showcase avenues for therapeutic interventions.

  6. Encefalopatia traumática crônica do boxeador (dementia pugilistica Chronic traumatic encephalopathy (dementia pugilistica of the box player

    Directory of Open Access Journals (Sweden)

    Renata Areza-Fegyveres

    2005-01-01

    Full Text Available A dementia pugilistica é caracterizada clinicamente por declínio cognitivo, alterações de comportamento e sinais parkinsonianos. Do ponto de vista neuropatológico, o achado mais marcante é o de numerosos emaranhados neurofibrilares no córtex cerebral na virtual ausência de placas senis. O objetivo deste artigo é apresentar revisão do tema, enfatizando as alterações cognitivas, epidemiologia, neuropatologia, estratégias de detecção precoce e relação com a doença de Alzheimer.Dementia pugilistica is characterized by cognitive decline, behavioral changes, and parkinsonian signs. The most remarkable neuropathological finding is the large amount of neurofibrillary tangles and virtual absence of senile plaques. The aim of the study is to revise the subject, particularly the clinical picture, epidemiology, neuropathology, the strategies for early detection of cognitive signs, and its relation with Alzheimer's disease.

  7. Neuronal Models for Studying Tau Pathology

    Directory of Open Access Journals (Sweden)

    Thorsten Koechling

    2010-01-01

    Full Text Available Alzheimer's disease (AD is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing -amyloid peptide and neurofibrillary tangles (NFTs, consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD.

  8. Heparin oligosaccharides as potential therapeutic agents in senile dementia.

    Science.gov (United States)

    Ma, Qing; Cornelli, Umberto; Hanin, Israel; Jeske, Walter P; Linhardt, Robert J; Walenga, Jeanine M; Fareed, Jawed; Lee, John M

    2007-01-01

    Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer's type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit anti-inflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents.

  9. Mild to Moderate Alzheimer Dementia with Insufficient Neuropathological Changes

    Science.gov (United States)

    Serrano-Pozo, Alberto; Qian, Jing; Monsell, Sarah E.; Blacker, Deborah; Gómez-lsla, Teresa; Betensky, Rebecca A.; Growdon, John H.; Johnson, Keith; Frosch, Matthew P.; Sperling, Reisa A.; Hyman, Bradley T.

    2014-01-01

    Recently, ∼16% of participants in an anti-Aβ passive immunotherapy trial for mild-to-moderate Alzheimer disease (AD) had a negative baseline amyloid positron emission tomography (PET) scan. Whether they have AD or are AD clinical phenocopies remains unknown. We examined the 2005-2013 National Alzheimer's Coordinating Center autopsy database and found that ∼14% of autopsied subjects clinically diagnosed with mild-to-moderate probable AD have no or sparse neuritic plaques, which would expectedly yield a negative amyloid PET scan. More than half of these “Aβ-negative” subjects have low neurofibrillary tangle Braak stages. These findings support the implementation of a positive amyloid biomarker as an inclusion criterion in future anti-Aβ drug trials. PMID:24585367

  10. Inflammation as a potential mediator for the association between periodontal disease and Alzheimer’s disease

    Science.gov (United States)

    Watts, Amber; Crimmins, Eileen M; Gatz, Margaret

    2008-01-01

    Periodontal disease (PDD) is associated with increased risk of cardiovascular disease, cerebrovascular disease, and mortality in many studies, while other studies have begun to suggest an association of PDD with Alzheimer’s disease (AD). This paper discusses how infectious pathogens and systemic infection may play a role in AD. The roles of infection and inflammation are addressed specifically with regard to known AD pathologic lesions including senile plaques, neuron death, neurofibrillary tangles, and cerebrovascular changes. A testable model of proposed pathways between periodontal infection and AD is presented including three possible mechanisms: a) direct effects of infectious pathogens, b) inflammatory response to pathogens, and c) the effects on vascular integrity. The role of gene polymorphisms is discussed, including apolipoprotein (APOE) ɛ4 as a pro-inflammatory and pro-infection genotype. PMID:19183779

  11. Metabolic profiling of Alzheimer's disease brains

    Science.gov (United States)

    Inoue, Koichi; Tsutsui, Haruhito; Akatsu, Hiroyasu; Hashizume, Yoshio; Matsukawa, Noriyuki; Yamamoto, Takayuki; Toyo'Oka, Toshimasa

    2013-08-01

    Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.

  12. A Culture-Brain Link: Negative Age Stereotypes Predict Alzheimer’s-disease Biomarkers

    Science.gov (United States)

    Levy, Becca R.; Ferrucci, Luigi; Zonderman, Alan B.; Slade, Martin D.; Troncoso, Juan; Resnick, Susan M.

    2016-01-01

    Although negative age stereotypes have been found to predict adverse outcomes among older individuals, it was unknown whether the influence of stereotypes extends to brain changes associated with Alzheimer’s disease. To consider this possibility, we drew on the age stereotypes of dementia-free participants in the Baltimore Longitudinal Study of Aging that had been measured decades before yearly MRIs and brain autopsies were performed. Those with more negative age stereotypes earlier in life had significantly steeper hippocampal-volume loss, and significantly greater accumulation of neurofibrillary tangles and amyloid plaques at autopsy, adjusting for relevant covariates. These findings suggest a new pathway to identifying mechanisms and potential interventions related to the neuropathology of Alzheimer’s disease. PMID:26641877

  13. Neurogenesis and Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disease, characterized in the brain by amyloid plaque deposits and neurofibrillary tangles. It is the most common form of dementia among older people. There is at present no cure for AD, and current treatments consist mainly in drug therapy. Potential therapies for AD involve gene and cellular therapy. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs reside in the adult central nervous system (CNS provide new opportunities for cellular therapy in the CNS, particularly for AD, and to better understand brain physiopathology. Hence, researchers have aimed at characterizing neurogenesis in patients with AD. Studies show that neurogenesis is increased in these patients, and in animal models of AD. The effect of drugs used to treat AD on neurogenesis is currently being investigated, to identify whether neurogenesis contributes to their therapeutic activities.

  14. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

    Science.gov (United States)

    Revett, Timothy J.; Baker, Glen B.; Jhamandas, Jack; Kar, Satyabrata

    2013-01-01

    Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid β peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid β and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid β production, but also amyloid β can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness. PMID:22894822

  15. Glutamate system, amyloid ß peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology.

    Science.gov (United States)

    Revett, Timothy J; Baker, Glen B; Jhamandas, Jack; Kar, Satyabrata

    2013-01-01

    Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid ß peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid ß and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid ß production, but also amyloid ß can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness.

  16. Repeated intraperitoneal injections of liposomes containing phosphatidic acid and cardiolipin reduce amyloid-β levels in APP/PS1 transgenic mice

    DEFF Research Database (Denmark)

    Ordóñez-Gutiérrez, Lara; Re, Francesca; Bereczki, Erika

    2015-01-01

    UNLABELLED: The accumulation of extracellular amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). It is thought that an equilibrium exists between Aβ in the brain and in the peripheral blood and thus......, it was hypothesized that shifting this equilibrium towards the blood by enhancing peripheral clearance might reduce Aβ levels in the brain: the 'sink effect'. We tested this hypothesis by intraperitoneally injecting APP/PS1 transgenic mice with small unilamellar vesicles containing either phosphatidic acid...... Aβ may be therapeutically relevant in AD. FROM THE CLINICAL EDITOR: Intraperitoneal injection of small unilamellar vesicles containing phosphatidic acid or cardiolipin significantly reduced the amount of amyloid-beta (Aß) peptide in the plasma in a rodent model. Brain levels of Aß were also affected...

  17. Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity

    DEFF Research Database (Denmark)

    Rusu, Patricia; Jansen, Anna; Soba, Peter

    2007-01-01

    Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular plaques, which consist mainly of beta-amyloid derived from the beta-amyloid precursor protein (APP). An additional feature of AD is axonopathy, which might contribute to impairment of cognitive functions....... Specifically, axonal transport defects have been reported in AD animal models, including mice and flies that overexpress APP and tau. Here we demonstrate that the APP-induced traffic jam of vesicles in peripheral nerves of Drosophila melanogaster larvae depends on the four residues NPTY motif in the APP....... Together, our results show that overexpression of APP induces partial stalling of axonal transport vesicles, paralleled by abnormalities in synaptic plasticity, which may provide a functional link to the deterioration of cognitive functions observed in AD....

  18. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

    Directory of Open Access Journals (Sweden)

    Steven Moore

    2015-05-01

    Full Text Available Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD. To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.

  19. The role of amyloid-beta in the regulation of memory.

    Science.gov (United States)

    Morley, John E; Farr, Susan A

    2014-04-15

    In this review there is evidence that amyloid-beta peptide is a memory enhancer at physiological (picomolar) concentrations. Pathological overproduction of amyloid-beta leads to impaired memory, oxidative damage, damage to the blood brain barrier, neurofibrillary tangles and amyloid plaque formation. Antisenses to amyloid precursor protein (APP) can reverse these effects in mice when they lower amyloid-beta protein to physiological levels. Data suggests that overproduction of APP leads to oxidative stress producing a vicious cycle of neuronal damage. For these reasons we have revised the "amyloid cascade hypothesis" removing emphasis from the plaque to amyloid-beta overproduction and suggest that an "amyloid-beta mitochondrial vicious cycle" hypothesis may be a better pathophysiological model for understanding Alzheimer's disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models

    Science.gov (United States)

    Zhang, Bei; Wang, Ying; Li, Hui; Xiong, Ran; Zhao, Zongbo; Chu, Xingkun; Li, Qiongqiong; Sun, Suya; Chen, Shengdi

    2016-01-01

    Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by deposits of aggregated amyloid-β (Aβ) peptide and neurofibrillary tangles in the brain parenchyma. Despite considerable research to elucidate the pathological mechanisms and identify therapeutic strategies for AD, effective treatments are still lacking. In the present study, we found that salidroside (Sal), a phenylpropanoid glycoside isolated from Rhodiola rosea L., can protect against Aβ-induced neurotoxicity in four transgenic Drosophila AD models. Both longevity and locomotor activity were improved in Sal-fed Drosophila. Sal also decreased Aβ levels and Aβ deposition in brain and ameliorated toxicity in Aβ-treated primary neuronal culture. The neuroprotective effect of Sal was associated with upregulated phosphatidylinositide 3-kinase (PI3K)/Akt signaling. Our findings identify a compound that may possess potential therapeutic benefits for AD and other forms of neurodegeneration. PMID:27103787

  1. More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases.

    Science.gov (United States)

    Lee, Virginia M-Y; Giasson, Benoit I; Trojanowski, John Q

    2004-03-01

    Intracytoplasmic filamentous aggregates, such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease, are composed of the proteins tau and alpha-synuclein, respectively. These pathological inclusions are linked directly to the etiology and mechanisms of disease in a wide spectrum of neurodegenerative disorders, termed 'tauopathies' and 'synucleinopathies'. Emerging evidence indicates that there is frequent overlap of the pathological and clinical features of patients with tauopathies and synucleinopathies, thereby re-enforcing the notion that these disorders might be linked mechanistically. Indeed, several lines of investigation suggest that tau and alpha-synuclein might constitute a unique class of unstructured proteins that assemble predominantly into homopolymeric (rather than heteropolymeric) fibrils, which deposit mainly in separate amyloid inclusions, but occasionally deposit together. Thus, the ability of tau and alpha-synuclein to affect each other directly or indirectly might contribute to the overlap in the clinical and pathological features of tauopathies and synucleinopathies.

  2. Trophic Tangles through Time? Opposing Direct and Indirect Effects of an Invasive Omnivore on Stream Ecosystem Processes

    Science.gov (United States)

    Moore, Jonathan W.; Carlson, Stephanie M.; Twardochleb, Laura A.; Hwan, Jason L.; Fox, Justin M.; Hayes, Sean A.

    2012-01-01

    Omnivores can impact ecosystems via opposing direct or indirect effects. For example, omnivores that feed on herbivores and plants could either increase plant biomass due to the removal of herbivores or decrease plant biomass due to direct consumption. Thus, empirical quantification of the relative importance of direct and indirect impacts of omnivores is needed, especially the impacts of invasive omnivores. Here we investigated how an invasive omnivore (signal crayfish, Pacifastacus leniusculus) impacts stream ecosystems. First, we performed a large-scale experiment to examine the short-term (three month) direct and indirect impacts of crayfish on a stream food web. Second, we performed a comparative study of un-invaded areas and areas invaded 90 years ago to examine whether patterns from the experiment scaled up to longer time frames. In the experiment, crayfish increased leaf litter breakdown rate, decreased the abundance and biomass of other benthic invertebrates, and increased algal production. Thus, crayfish controlled detritus via direct consumption and likely drove a trophic cascade through predation on grazers. Consistent with the experiment, the comparative study also found that benthic invertebrate biomass decreased with crayfish. However, contrary to the experiment, crayfish presence was not significantly associated with higher leaf litter breakdown in the comparative study. We posit that during invasion, generalist crayfish replace the more specialized native detritivores (caddisflies), thereby leading to little long-term change in net detrital breakdown. A feeding experiment revealed that these native detritivores and the crayfish were both effective consumers of detritus. Thus, the impacts of omnivores represent a temporally-shifting interplay between direct and indirect effects that can control basal resources. PMID:23209810

  3. The Principal's Quick-Reference Guide to School Law: Reducing Liability, Litigation, and Other Potential Legal Tangles.

    Science.gov (United States)

    Dunklee, Dennis R.; Shoop, Robert J.

    This book is designed to inform school administrators regarding school law. As a resource, it provides suggested, easy-to-understand guidelines for the avoidance of litigation. Subjects include preventive law and risk management; constitutional and statutory foundations of staff selection, contracting, and evaluation; negligent hiring, defamation,…

  4. Conflicts of Interest and Incentives to Bias: A Microeconomic Critique of Google’s Tangled Position on the Web

    NARCIS (Netherlands)

    Rieder, B.; Sire, G.

    2014-01-01

    Media scholars have studied and critiqued search engines - and in particular the dominant commercial actor, Google - for over a decade. Several conceptual and methodological problems, such as a lack of technological transparency, have made a detailed analysis of concrete power relations and their

  5. A tangled tale of two teal: Population history of the grey Anas gracilis and chestnut teal a. castanea of Australia

    Science.gov (United States)

    Joseph, L.; Adcock, G.J.; Linde, C.; Omland, K.E.; Heinsohn, R.; Terry, Chesser R.; Roshier, D.

    2009-01-01

    Two Australian species of teal (Anseriformes: Anatidae: Anas), the grey teal Anas gracilis and the chestnut teal A. castanea, are remarkable for the zero or near-zero divergence recorded between them in earlier surveys of mitochondrial DNA (mtDNA) diversity. We confirmed this result through wider geographical and population sampling as well as nucleotide sampling in the more rapidly evolving mtDNA control region. Any data set where two species share polymorphism as is the case here can be explained by a model of gene flow through hybridization on one hand or by incomplete lineage sorting on the other hand. Ideally, analysis of such shared polymorphism would simultaneously estimate the likelihood of both phenomena. To do this, we used the underlying principle of the IMa package to explore ramifications to understanding population histories of A. gracilis and A. castanea. We cannot reject that hybridization occurs between the two species but an equally or more plausible finding for their nearly zero divergence is incomplete sorting following very recent divergence between the two, probably in the mid-late Pleistocene. Our data add to studies that explore intermediate stages in the evolution of reciprocal monophyly and paraphyletic or polyphyletic relationships in mtDNA diversity among widespread Australian birds. ?? 2009 J. Avian Biol.

  6. WORKING MIS/UNDERSTANDINGS: The Tangled Relationship between Kinship, Franco‐Malagasy Binational Marriages, and the French State

    National Research Council Canada - National Science Library

    COLE, JENNIFER

    2014-01-01

    .... Based on extensive research with Franco‐Malagasy families in southwestern France, this article examines how couples negotiate the complexities of their binational relationships in the context of state...

  7. The Tangled Tale of Genes and Environment: Moore's The Dependent Gene: The Fallacy of “nature VS. Nurture”

    Science.gov (United States)

    Schneider, Susan M

    2007-01-01

    Nature–nurture views that smack of genetic determinism remain prevalent. Yet, the increasing knowledge base shows ever more clearly that environmental factors and genes form a fully interactional system at all levels. Moore's book covers the major topics of discovery and dispute, including behavior genetics and the twin studies, developmental psychobiology, and developmental systems theory. Knowledge of this larger life-sciences context for behavior principles will become increasingly important as the full complexity of gene–environment relations is revealed. Behavior analysis both contributes to and gains from the larger battle for the recognition of how nature and nurture really work.

  8. The Tangled Tale of Genes and Environment: Moore's The Dependent Gene: The Fallacy of “nature VS. Nurture”

    OpenAIRE

    Schneider, Susan M.

    2007-01-01

    Nature–nurture views that smack of genetic determinism remain prevalent. Yet, the increasing knowledge base shows ever more clearly that environmental factors and genes form a fully interactional system at all levels. Moore's book covers the major topics of discovery and dispute, including behavior genetics and the twin studies, developmental psychobiology, and developmental systems theory. Knowledge of this larger life-sciences context for behavior principles will become increasingly importa...

  9. THE EFFECTS OF ABSTRACTION ON INTEGRATIVE AGREEMENTS: WHEN SEEING THE FOREST HELPS AVOID GETTING TANGLED IN THE TREES

    Science.gov (United States)

    Henderson, Marlone D.; Trope, Yaacov

    2011-01-01

    The present research suggests that negotiators who represented negotiation issues more abstractly were more likely to reach integrative agreements. Specifically, participants who were prompted to directly think about their negotiation issues in a more abstract manner by generating general descriptions of the issues rather than more concretely about the negotiation issues by generating specific descriptions of the issues made more multi-issue offers and achieved higher joint gain from the negotiation. The role of abstraction in negotiation and conflict resolution is discussed. PMID:21836768

  10. Current and emerging global themes in the bioethics of regenerative medicine: the tangled web of stem cell translation.

    Science.gov (United States)

    Chan, Sarah

    2017-10-01

    Probably the most serious problem facing the field of regenerative medicine today is the challenge of effective translation and development of viable stem cell-based therapies. Particular concerns have been raised over the growing market in unproven cell therapies. In this article, I explore recent developments in the stem cell therapy landscape and argue that while the sale of unproven therapies undoubtedly poses ethical concerns, it must be understood as part of a larger problem at the interface between biomedicine, healthcare, publics, policy and the market. Addressing this will require a broader perspective incorporating the shifting relationships between different stakeholder groups, the global politics of research and innovation, and the evolving role of publics and patients with respect to science.

  11. 76 FR 16807 - Notice of Intent To Collect Fees on Public Land in Tangle Lakes, Alaska, Glennallen Field Office...

    Science.gov (United States)

    2011-03-25

    ... recreation fee business plan; consultation with the BLM Anchorage District Office; and the public being... charged an ``Expanded Amenity Recreation Fee.'' Pursuant to the REA and regulations at 43 CFR part 2931... and resource protection. The amount of the recreation fee shall be commensurate with fees charged at...

  12. Tangled in a Complex Web of Relationships: Athletic/Academic Advisors Negotiating Privacy Disclosure Warnings with College Student-Athletes

    Science.gov (United States)

    Thompson, Jason

    2013-01-01

    To investigate privacy management in the relationship between athletic/academic advisors and college student-athletes, I interviewed 37 advisors to address the following questions: What type of privacy rules do student-athletes communicate to advisors? How do advisors manage student-athletes' private information following these rules?…

  13. Trophic tangles through time? Opposing direct and indirect effects of an invasive omnivore on stream ecosystem processes.

    Directory of Open Access Journals (Sweden)

    Jonathan W Moore

    Full Text Available Omnivores can impact ecosystems via opposing direct or indirect effects. For example, omnivores that feed on herbivores and plants could either increase plant biomass due to the removal of herbivores or decrease plant biomass due to direct consumption. Thus, empirical quantification of the relative importance of direct and indirect impacts of omnivores is needed, especially the impacts of invasive omnivores. Here we investigated how an invasive omnivore (signal crayfish, Pacifastacus leniusculus impacts stream ecosystems. First, we performed a large-scale experiment to examine the short-term (three month direct and indirect impacts of crayfish on a stream food web. Second, we performed a comparative study of un-invaded areas and areas invaded 90 years ago to examine whether patterns from the experiment scaled up to longer time frames. In the experiment, crayfish increased leaf litter breakdown rate, decreased the abundance and biomass of other benthic invertebrates, and increased algal production. Thus, crayfish controlled detritus via direct consumption and likely drove a trophic cascade through predation on grazers. Consistent with the experiment, the comparative study also found that benthic invertebrate biomass decreased with crayfish. However, contrary to the experiment, crayfish presence was not significantly associated with higher leaf litter breakdown in the comparative study. We posit that during invasion, generalist crayfish replace the more specialized native detritivores (caddisflies, thereby leading to little long-term change in net detrital breakdown. A feeding experiment revealed that these native detritivores and the crayfish were both effective consumers of detritus. Thus, the impacts of omnivores represent a temporally-shifting interplay between direct and indirect effects that can control basal resources.

  14. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice

    Directory of Open Access Journals (Sweden)

    LaFerla Frank M

    2005-10-01

    Full Text Available Abstract Background Alzheimer's disease is a complex neurodegenerative disorder characterized pathologically by a temporal and spatial progression of beta-amyloid (Aβ deposition, neurofibrillary tangle formation, and synaptic degeneration. Inflammatory processes have been implicated in initiating and/or propagating AD-associated pathology within the brain, as inflammatory cytokine expression and other markers of inflammation are pronounced in individuals with AD pathology. The current study examines whether inflammatory processes are evident early in the disease process in the 3xTg-AD mouse model and if regional differences in inflammatory profiles exist. Methods Coronal brain sections were used to identify Aβ in 2, 3, and 6-month 3xTg-AD and non-transgenic control mice. Quantitative real-time RT-PCR was performed on microdissected entorhinal cortex and hippocampus tissue of 2, 3, and 6-month 3xTg-AD and non-transgenic mice. Microglial/macrophage cell numbers were quantified using unbiased stereology in 3xTg-AD and non-transgenic entorhinal cortex and hippocampus containing sections. Results We observed human Aβ deposition at 3 months in 3xTg-AD mice which is enhanced by 6 months of age. Interestingly, we observed a 14.8-fold up-regulation of TNF-α and 10.8-fold up-regulation of MCP-1 in the entorhinal cortex of 3xTg-AD mice but no change was detected over time in the hippocampus or in either region of non-transgenic mice. Additionally, this increase correlated with a specific increase in F4/80-positive microglia and macrophages in 3xTg-AD entorhinal cortex. Conclusion Our data provide evidence for early induction of inflammatory processes in a model that develops amyloid and neurofibrillary tangle pathology. Additionally, our results link inflammatory processes within the entorhinal cortex, which represents one of the earliest AD-affected brain regions.

  15. Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy

    Directory of Open Access Journals (Sweden)

    Gozes I

    2012-02-01

    Full Text Available Michael Gold1, Stefan Lorenzl2, Alistair J Stewart1, Bruce H Morimoto1, David R Williams3, Illana Gozes1,41Allon Therapeutics Inc, Vancouver, BC, Canada; 2Interdisciplinary Center for Palliative Medicine, Munich University Hospital Klinikum Grosshadern, Munich, Germany; 3Van Cleef/Roet Centre for Nervous Diseases, Monash University, Melbourne, Australia; 4The Dr Diana and Zelman Elton (Elbaum Laboratory for Molecular Neuroendocrinology, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Adams Super Center for Brain Studies, and the Department of Human Molecular Genetics and Biochemistry, School of Neuroscience, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelAbstract: Progressive supranuclear palsy (PSP is a rare neurodegenerative disease characterized by the accumulation of tau protein aggregates in the basal ganglia, brainstem and cerebral cortex leading to rapid disease progression and death. The neurofibrillary tangles that define the neuropathology of PSP are comprised of aggregated 4R tau and show a well-defined distribution. Classically, PSP is diagnosed by symptoms that include progressive gait disturbance, early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. There are currently no effective therapies for the treatment of this rapidly degenerating and debilitating disease. Davunetide is a novel neuroprotective peptide that is thought to impact neuronal integrity and cell survival through the stabilization of microtubules. Preclinical activity in models of tauopathy has been translated to clinical studies, demonstrating pharmacologic activity that has supported further development. Davunetide's efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for

  16. Localized cortical chronic traumatic encephalopathy pathology after single, severe axonal injury in human brain.

    Science.gov (United States)

    Shively, Sharon B; Edgerton, Sarah L; Iacono, Diego; Purohit, Dushyant P; Qu, Bao-Xi; Haroutunian, Vahram; Davis, Kenneth L; Diaz-Arrastia, Ramon; Perl, Daniel P

    2017-03-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild impact traumatic brain injury from contact sports. Recently, a consensus panel defined the pathognomonic lesion for CTE as accumulations of abnormally hyperphosphorylated tau (p-tau) in neurons (neurofibrillary tangles), astrocytes and cell processes distributed around small blood vessels at sulcal depths in irregular patterns within the cortex. The pathophysiological mechanism for this lesion is unknown. Moreover, a subset of CTE cases harbors cortical β-amyloid plaques. In this study, we analyzed postmortem brain tissues from five institutionalized patients with schizophrenia and history of surgical leucotomy with subsequent survival of at least another 40 years. Because leucotomy involves severing axons bilaterally in prefrontal cortex, this surgical procedure represents a human model of single traumatic brain injury with severe axonal damage and no external impact. We examined cortical tissues at the leucotomy site and at both prefrontal cortex rostral and frontal cortex caudal to the leucotomy site. For comparison, we analyzed brain tissues at equivalent neuroanatomical sites from non-leucotomized patients with schizophrenia, matched in age and gender. All five leucotomy cases revealed severe white matter damage with dense astrogliosis at the axotomy site and also neurofibrillary tangles and p-tau immunoreactive neurites in the overlying gray matter. Four cases displayed p-tau immunoreactivity in neurons, astrocytes and cell processes encompassing blood vessels at cortical sulcal depths in irregular patterns, similar to CTE. The three cases with apolipoprotein E ε4 haplotype showed scattered β-amyloid plaques in the overlying gray matter, but not the two cases with apolipoprotein E ε3/3 genotype. Brain tissue samples from prefrontal cortex rostral and frontal cortex caudal to the leucotomy site, and all cortical samples from the non-leucotomized patients

  17. Alzheimer's Disease Sequencing Project discovery and replication criteria for cases and controls: Data from a community-based prospective cohort study with autopsy follow-up.

    Science.gov (United States)

    Crane, Paul K; Foroud, Tatiana; Montine, Thomas J; Larson, Eric B

    2017-12-01

    The Alzheimer's Disease Sequencing Project (ADSP) used different criteria for assigning case and control status from the discovery and replication phases of the project. We considered data from a community-based prospective cohort study with autopsy follow-up where participants could be categorized as case, control, or neither by both definitions and compared the two sets of criteria. We used data from the Adult Changes in Thought (ACT) study including Diagnostic and Statistical Manual-IV criteria for dementia status, McKhann et al. criteria for clinical Alzheimer's disease, and Braak and Consortium to Establish a Registry for AD findings on neurofibrillary tangles and neuritic plaques to categorize the 621 ACT participants of European ancestry who died and came to autopsy. We applied ADSP discovery and replication definitions to identify controls, cases, and people who were neither controls nor cases. There was some agreement between the discovery and replication definitions. Major areas of discrepancy included the finding that only 40% of the discovery sample controls had sufficiently low levels of neurofibrillary tangles and neuritic plaques to be considered controls by the replication criteria and the finding that 16% of the replication phase cases were diagnosed with non-AD dementia during life and thus were excluded as cases for the discovery phase. These findings should inform interpretation of genetic association findings from the ADSP. Differences in genetic association findings between the two phases of the study may reflect these different phenotype definitions from the discovery and replication phase of the ADSP. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  18. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines

    Directory of Open Access Journals (Sweden)

    C. Dirk Keene

    2016-06-01

    Full Text Available Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD, have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1 cerebrospinal fluid (CSF AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2 structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG, and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3 cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines

  19. Targeting brain α7 nicotinic acetylcholine receptors in Alzheimer's disease: rationale and current status.

    Science.gov (United States)

    Vallés, Ana Sofía; Borroni, María Virginia; Barrantes, Francisco J

    2014-11-01

    Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the α7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-β-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the α7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target α7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, α7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors.

  20. Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Lambracht-Washington D

    2013-08-01

    Full Text Available Doris Lambracht-Washington, Roger N Rosenberg Department of Neurology and Neurotherapeutics, Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA Abstract: Immunotherapy might provide an effective treatment for Alzheimer's disease (AD. A unique feature of AD immunotherapies is that an immune response against a self-antigen needs to be elicited without causing adverse autoimmune reactions. Current research is focused on two possible targets in this regard. One is the inhibition of accumulation and deposition of amyloid beta 1–42 (Aβ42, which is one of the major peptides found in senile plaques, and the second target is hyperphosphorylated tau, which forms neurofibrillary tangles inside the nerve cell and shows association with the progression of dementia. Mouse models have shown that immunotherapy targeting Aβ42 as well as tau with the respective anti-Aβ or anti-tau antibodies can provide significant improvements in these mice. While anti-Aβ immunotherapy (active and passive immunizations is already in several stages of clinical trials, tau-based immunizations have been analyzed only in mouse models. Recently, as a significant correlation of progression of dementia and levels of phosphorylated tau have been found, high interest has again focused on further development of tau-based therapies. While Aβ immunotherapy might delay the onset of AD, immunotherapy targeting tau might provide benefits in later stages of this disease. Last but not least, targeting Aβ and tau simultaneously with immunotherapy might provide additional therapeutic effects, as these two pathologies are likely synergistic; this is an approach that has not been tested yet. In this review, we will summarize animal models used to test possible therapies for AD, some of the facts about Aβ42 and tau biology, and present an overview on halted, ongoing, and upcoming clinical trials together with ongoing preclinical studies targeting tau

  1. Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines.

    Science.gov (United States)

    Keene, C Dirk; Darvas, Martin; Kraemer, Brian; Liggitt, Denny; Sigurdson, Christina; Ladiges, Warren

    2016-01-01

    Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards

  2. The role of protein glycosylation in Alzheimer disease.

    Science.gov (United States)

    Schedin-Weiss, Sophia; Winblad, Bengt; Tjernberg, Lars O

    2014-01-01

    Glycosylation is one of the most common, and the most complex, forms of post-translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid β-peptide (Aβ), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid β-peptide (Aβ), i.e. γ-secretase and β-secretase, also have roles in protein glycosylation. For instance, γ-secretase and β-secretase affect the extent of complex N-glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of γ-secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v-ATPase, and tyrosine-related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients. © 2013 FEBS.

  3. New Features about Tau Function and Dysfunction

    Science.gov (United States)

    Medina, Miguel; Hernández, Félix; Avila, Jesús

    2016-01-01

    Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD). Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future. PMID:27104579

  4. Aluminum and Alzheimer's disease: a new look.

    Science.gov (United States)

    Miu, Andrei C; Benga, Oana

    2006-11-01

    Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the neuropathological dissociation between AD and dialysis associated encephalopathy, and the epidemiological relations between Al in drinking water and the prevalence of AD. We also critically analyze the prospects of Al-amyloid cascade studies and other evolving lines of evidence that might shed insights into the link between Al and AD. The message between the lines of the following article is that the involvement of Al in the pathogenesis of AD should not be discarded, especially in these times when the amyloid dogma of AD etiology shows its myopia.

  5. Aluminum involvement in the progression of Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2013-01-01

    The neuroanatomic specificity with which Alzheimer's disease (AD) progresses could provide clues to AD etiopathology. Magnetic resonance imaging studies of AD clinical progression have confirmed general conclusions from earlier studies of AD neuropathological progression wherein neurofibrillary tangle pathology was observed to spread along a well-defined sequence of corticocortical and corticosubcortical connections, preferentially affecting certain cell types, while sparing others. Identical and non-identical twin studies have consistently shown AD has mixed (environmental and genetic) etiopathogenesis. The decades-long prodromal phase over which AD develops suggests slow but progressive accumulation of a toxic or infective agent over time. Major environmental candidates are reviewed to assess which best fits the profile of an agent that slowly accrues in susceptible cell types of AD-vulnerable brain regions to toxic levels by old age, giving rise to AD neuropathology without rapid neuronal lysis. Chronic aluminum neurotoxicity best matches this profile. Many humans routinely ingest aluminum salts as additives contained in processed foods and alum-treated drinking water. The physical properties of aluminum and ferric iron ions are similar, allowing aluminum to use mechanisms evolved for iron to enter vulnerable neurons involved in AD progression, accumulate in those neurons, and cause neurofibrillary damage. The genetic component of AD etiopathogenesis apparently involves a susceptibility gene, yet to be identified, that increases aluminum absorption because AD and Down syndrome patients have higher than normal plasma, and brain, aluminum levels. This review describes evidence for aluminum involvement in AD neuropathology and the clinical progression of sporadic AD.

  6. TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

    Science.gov (United States)

    McKee, Ann C.; Gavett, Brandon E.; Stern, Robert A.; Nowinski, Christopher J.; Cantu, Robert C.; Kowall, Neil W.; Perl, Daniel P.; Hedley-Whyte, E. Tessa; Price, Bruce; Sullivan, Chris; Morin, Peter; Lee, Hyo-Soon; Kubilus, Caroline A.; Daneshvar, Daniel H.; Wulff, Megan; Budson, Andrew E.

    2010-01-01

    Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease. PMID:20720505

  7. Modeling familial Danish dementia in mice supports the concept of the amyloid hypothesis of Alzheimer's disease

    Science.gov (United States)

    Coomaraswamy, Janaky; Kilger, Ellen; Wölfing, Heidrun; Schäfer, Claudia; Kaeser, Stephan A.; Wegenast-Braun, Bettina M.; Hefendehl, Jasmin K.; Wolburg, Hartwig; Mazzella, Matthew; Ghiso, Jorge; Goedert, Michel; Akiyama, Haruhiko; Garcia-Sierra, Francisco; Wolfer, David P.; Mathews, Paul M.; Jucker, Mathias

    2010-01-01

    Familial Danish dementia (FDD) is a progressive neurodegenerative disease with cerebral deposition of Dan-amyloid (ADan), neuroinflammation, and neurofibrillary tangles, hallmark characteristics remarkably similar to those in Alzheimer's disease (AD). We have generated transgenic (tg) mouse models of familial Danish dementia that exhibit the age-dependent deposition of ADan throughout the brain with associated amyloid angiopathy, microhemorrhage, neuritic dystrophy, and neuroinflammation. Tg mice are impaired in the Morris water maze and exhibit increased anxiety in the open field. When crossed with TauP301S tg mice, ADan accumulation promotes neurofibrillary lesions, in all aspects similar to the Tau lesions observed in crosses between β-amyloid (Aβ)-depositing tg mice and TauP301S tg mice. Although these observations argue for shared mechanisms of downstream pathophysiology for the sequence-unrelated ADan and Aβ peptides, the lack of codeposition of the two peptides in crosses between ADan- and Aβ-depositing mice points also to distinguishing properties of the peptides. Our results support the concept of the amyloid hypothesis for AD and related dementias, and suggest that different proteins prone to amyloid formation can drive strikingly similar pathogenic pathways in the brain. PMID:20385796

  8. New Features about Tau Function and Dysfunction

    Directory of Open Access Journals (Sweden)

    Miguel Medina

    2016-04-01

    Full Text Available Tau is a brain microtubule-associated protein that directly binds to a microtubule and dynamically regulates its structure and function. Under pathological conditions, tau self-assembles into filamentous structures that end up forming neurofibrillary tangles. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders, collectively referred to as tauopathies, the most common of which is Alzheimer’s disease (AD. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have revealed novel insights into their important role during pathogenesis and provided potential novel therapeutic targets. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, including phosphorylation, glycosylation, acetylation, and truncation, among others, indicating the complexity and variability of factors influencing regulation of tau toxicity, all of which have significant implications for the development of novel therapeutic approaches in various neurodegenerative disorders. A more comprehensive understanding of the molecular mechanisms regulating tau function and dysfunction will provide us with a better outline of tau cellular networking and, hopefully, offer new clues for designing more efficient approaches to tackle tauopathies in the near future.

  9. Age, Alzheimer's disease and dementia in the Baltimore Longitudinal Study of Ageing.

    Science.gov (United States)

    Dolan, David; Troncoso, Juan; Resnick, Susan M; Crain, Barbara J; Zonderman, Alan B; O'Brien, Richard J

    2010-08-01

    Recent studies suggest that dementia in the most elderly (90 years of age and above) is only modestly related to Alzheimer's disease pathology. This raises the possibility that other, as yet unknown, disease processes may underlie dementia in this rapidly growing demographic group, and that efforts designed to combat Alzheimer's disease may not be appropriate for treating dementia in very elderly subjects. To study this question more closely, we examined the relationship between neocortical Alzheimer-type brain pathology and dementia in consecutive autopsies from 209 participants in the Baltimore Longitudinal Study of Ageing, a prospective longitudinal cohort study of the effect of ageing on cognition. Almost half of the cohort was older than 90 years of age at death. We found that several measures of neocortical Alzheimer's pathology, including the Consortium to Establish a Registry of Alzheimer's Disease neuritic plaque score and the Braak neurofibrillary tangle score, remained significant predictors of dementia, independent of age. In participants older than 90 years of age, intracranial atherosclerosis emerged as an important predictor of dementia in subjects with low Alzheimer's pathology scores, but did not mitigate the importance or population attributable risk of high Alzheimer's pathology scores on the odds of dementia. There was evidence that the threshold score for neurofibrillary pathology to cause dementia increased in the oldest subjects, but this was offset by an overall increase in neurofibrillary pathology in this age group. We conclude that neocortical Alzheimer's disease pathology remains significantly correlated with dementia, independent of age. In the most elderly, atherosclerosis also emerged as a cause of dementia in subjects with low Alzheimer's pathology scores. We found no evidence for a significant number of elderly subjects having dementia without an apparent cause.

  10. Tau hyperphosphorylation in synaptosomes and neuroinflammation are associated with canine cognitive impairment.

    Science.gov (United States)

    Smolek, Tomas; Madari, Aladar; Farbakova, Jana; Kandrac, Ondrej; Jadhav, Santosh; Cente, Martin; Brezovakova, Veronika; Novak, Michal; Zilka, Norbert

    2016-03-01

    Canine cognitive impairment syndrome (CDS) represents a group of symptoms related to the aging of the canine brain. These changes ultimately lead to a decline of memory function and learning abilities, alteration of social interaction, impairment of normal housetraining, and changes in sleep-wake cycle and general activity. We have clinically examined 215 dogs, 28 of which underwent autopsy. With canine brains, we performed extensive analysis of pathological abnormalities characteristic of human Alzheimer's disease and frontotemporal lobar degeneration, including β-amyloid senile plaques, tau neurofibrillary tangles, and fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP43) inclusions. Most demented dogs displayed senile plaques, mainly in the frontal and temporal cortex. Tau neurofibrillary inclusions were found in only one dog. They were identified with antibodies used to detect tau neurofibrillary lesions in the human brain. The inclusions were also positive for Gallyas silver staining. As in humans, they were distributed mainly in the entorhinal cortex, hippocampus, and temporal cortex. On the other hand, FUS and TDP43 aggregates were not present in any of the examined brain samples. We also found that CDS was characterized by the presence of reactive and senescent microglial cells in the frontal cortex. Our transcriptomic study revealed a significant dysregulation of genes involved in neuroinflammation. Finally, we analyzed tau phosphoproteome in the synaptosomes. Proteomic studies revealed a significant increase of hyperphosphorylated tau in synaptosomes of demented dogs compared with nondemented dogs. This study suggests that cognitive decline in dogs is related to the tau synaptic impairment and neuroinflammation. J. Comp. Neurol. 524:874-895, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  11. Changes in CD200 and intercellular adhesion molecule-1 (ICAM-1) levels in brains of Lewy body disorder cases are associated with amounts of Alzheimer's pathology not α-synuclein pathology.

    Science.gov (United States)

    Walker, Douglas G; Lue, Lih-Fen; Tang, Tiffany M; Adler, Charles H; Caviness, John N; Sabbagh, Marwan N; Serrano, Geidy E; Sue, Lucia I; Beach, Thomas G

    2017-06-01

    Enhanced inflammation has been associated with Alzheimer's disease (AD) and diseases with Lewy body (LB) pathology, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). One issue is whether amyloid and tangle pathology, features of AD, or α-synuclein LB pathology have similar or different effects on brain inflammation. An aim of this study was to examine if certain features of inflammation changed in brains with increasing LB pathology. To assess this, we measured levels of the anti-inflammatory protein CD200 and the pro-inflammatory protein intercellular adhesion molecule-1 (ICAM-1) in cingulate and temporal cortex from a total of 143 cases classified according to the Unified Staging System for LB disorders. Changes in CD200 and ICAM-1 levels did not correlate with LB pathology, but with AD pathology. CD200 negatively correlated with density of neurofibrillary tangles, phosphorylated tau, and amyloid plaque density. ICAM-1 positively correlated with these AD pathology measures. Double immunohistochemistry for phosphorylated α-synuclein and markers for microglia showed limited association of microglia with LB pathology, but microglia strongly associated with amyloid plaques or phosphorylated tau. These results suggest that there are different features of inflammatory pathology in diseases associated with abnormal α-synuclein compared with AD. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Chronic Traumatic Encephalopathy: A Potential Late Effect of Sport-Related Concussive and Subconcussive Head Trauma1

    Science.gov (United States)

    Gavett, Brandon E.; Stern, Robert A.; McKee, Ann C.

    2010-01-01

    Synopsis Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration that is believed to result from repeated head injuries. Originally termed dementia pugilistica due to its association with boxing, the neuropathology of CTE was first described by Corsellis in 1973 in a case series of 15 retired boxers. CTE has recently been found to occur following other causes of repeated head trauma, suggesting that any repeated blows to the head, such as those that occur due to American football, hockey, soccer, professional wrestling, and physical abuse, can also lead to neurodegenerative changes. These changes often include cerebral atrophy, cavum septum pellucidum with fenestrations, shrinkage of the mammillary bodies, dense tau immunoreactive inclusions (neurofibrillary tangles, glial tangles, and neuropil neurites), diffuse axonal injury, and, in some cases, a TDP-43 proteinopathy. In association with these pathological changes, affected individuals often exhibit disordered memory and executive functioning, behavioral and personality disturbances (e.g., apathy, depression, irritability, impulsiveness, suicidality), parkinsonism, and, occasionally, motor neuron disease. At the present time, there are no formal clinical or pathological diagnostic criteria for CTE, but the distinctive neuropathological profile of the disorder lends promise for future research into its prevention, diagnosis, and treatment. PMID:21074091

  13. Is synaptic loss a unique hallmark of Alzheimer's disease?

    Science.gov (United States)

    Scheff, Stephen W.; Neltner, Janna H.; Nelson, Peter T.

    2014-01-01

    Synapses may represent a key nidus for dementia including Alzheimer's disease (AD) pathogenesis. Here we review published studies and present new ideas related to the question of the specificity of synapse loss in AD. Currently, AD is defined by the regional presence of neuritic plaques and neurofibrillary tangles in the brain. The severity of involvement by those pathological hallmarks tends to correlate both with antemortem cognitive status, and also with synapse loss in multiple brain areas. Recent studies from large autopsy series have led to a new standard of excellence with regard to clinical–pathological correlation and to improved comprehension of the numerous brain diseases of the elderly. These studies have provided evidence that it is the rule rather than the exception for brains of aged individuals to demonstrate pathologies (often multiple) other than AD plaques and tangles. For many of these comorbid pathologies, the extent of synapse loss is imperfectly understood but could be substantial. These findings indicate that synapse loss is probably not a hallmark specific to AD but rather a change common to many diseases associated with dementia. PMID:24412275

  14. The neuropathology of chronic traumatic encephalopathy.

    Science.gov (United States)

    McKee, Ann C; Stein, Thor D; Kiernan, Patrick T; Alvarez, Victor E

    2015-05-01

    Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE). Most instances of CTE occur in association with the play of sports, but CTE has also been reported in association with blast injuries and other neurotrauma. Symptoms of CTE include behavioral and mood changes, memory loss, cognitive impairment and dementia. Like many other neurodegenerative diseases, CTE is diagnosed with certainty only by neuropathological examination of brain tissue. CTE is a tauopathy characterized by the deposition of hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles, astrocytic tangles and neurites in striking clusters around small blood vessels of the cortex, typically at the sulcal depths. Severely affected cases show p-tau pathology throughout the brain. Abnormalities in phosphorylated 43 kDa TAR DNA-binding protein are found in most cases of CTE; beta-amyloid is identified in 43%, associated with age. Given the importance of sports participation and physical exercise to physical and psychological health as well as disease resilience, it is critical to identify the genetic risk factors for CTE as well as to understand how other variables, such as stress, age at exposure, gender, substance abuse and other exposures, contribute to the development of CTE. © 2015 International Society of Neuropathology.

  15. Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma.

    Science.gov (United States)

    Gavett, Brandon E; Stern, Robert A; McKee, Ann C

    2011-01-01

    Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration believed to result from repeated head injuries. Originally termed dementia pugilistica because of its association with boxing, the neuropathology of CTE was first described by Corsellis in 1973 in a case series of 15 retired boxers. CTE has recently been found to occur after other causes of repeated head trauma, suggesting that any repeated blows to the head, such as those that occur in American football, hockey, soccer, professional wrestling, and physical abuse, can also lead to neurodegenerative changes. These changes often include cerebral atrophy, cavum septi pellucidi with fenestrations, shrinkage of the mammillary bodies, dense tau immunoreactive inclusions (neurofibrillary tangles, glial tangles, and neuropil neurites), and, in some cases, a TDP-43 proteinopathy. In association with these pathologic changes, disordered memory and executive functioning, behavioral and personality disturbances (eg, apathy, depression, irritability, impulsiveness, suicidality), parkinsonism, and, occasionally, motor neuron disease are seen in affected individuals. No formal clinical or pathologic diagnostic criteria for CTE currently exist, but the distinctive neuropathologic profile of the disorder lends promise for future research into its prevention, diagnosis, and treatment. Published by Elsevier Inc.

  16. Comparison of the Effectiveness of Two Intervention Methods of Neurofeedback Training (NFT and the Movement Program on the Handwriting Performance of 9-11 Years Old Children with Dysgraphia

    Directory of Open Access Journals (Sweden)

    Saeid Arsham

    2017-12-01

    Full Text Available Abstract Background: Learning disorders, especially dysgraphia, are among the students' educational disabilities. The purpose of this study was to compare the effectiveness of two intervention methods of neurofeedback training and the movement program on the handwriting performance of 9-11 years old children with dysgraphia. Materials and Methods: This was a quasi-experimental comparative study with a pretest-posttest design. Thirty right-handed boy students aged 9 to 11 years old were selected from elementary and middle schools (district 4 in Karaj, based on the dysgraphia Fallahchai test. Participants were randomly divided into three groups each included 10 subjects. The movement program group did activities with emphasis on visual-motor coordination, fine motor control, visual-motor integrity, and eye-hand coordination 3 sessions per week, for 4 weeks (total of twelve sessions. The neurofeedback group did a training protocol (decreasing beta wave and increasing alpha wave at C3 zone in 4 weeks, 3 sessions per week each session for 20 minutes. The control group did not any training intervention. Results: The data analysis showed that there were significant differences between two groups of intervention and the control group. The two experimental groups had a significant improvement compared to the control group. Also, the results showed that the selected movement program is more effective than neurofeedback training intervention. Conclusion: Overall, the selected movement program was more effective than the neurofeedback training and control group. Therefore, it is suggested that the movement program intervention should be used to improve the handwriting performance of students with poor handwritten quality.

  17. Automatización de un cultivo hidropónico NFT para el control de temperatura, riego y mezcla de solución nutritiv, ubicada en la zona urbana de Quito

    OpenAIRE

    Rubio Mena, Carsten

    2017-01-01

    Over the years the human being has been looking for products that are increasingly natural, the technique of growing without soil or also called hydroponic crops is a solution for the growth of fruits, vegetables and vegetables, without the exposure of its root To the contamination of the soils, which are contaminated with different chemicals for their reuse making them fertile after their harvests. In Ecuador, the technique of hydroponics is little known, however in supermarkets there has be...

  18. Pathological conformations involving the amino terminus of tau occur early in Alzheimer's disease and are differentially detected by monoclonal antibodies.

    Science.gov (United States)

    Combs, Benjamin; Hamel, Chelsey; Kanaan, Nicholas M

    2016-10-01

    Conformational changes involving the amino terminus of the tau protein are among the earliest alterations associated with tau pathology in Alzheimer's disease and other tauopathies. This region of tau contains a phosphatase-activating domain (PAD) that is aberrantly exposed in pathological forms of the protein, an event that is associated with disruptions in anterograde fast axonal transport. We utilized four antibodies that recognize the amino terminus of tau, TNT1, TNT2 (a novel antibody), Tau12, and Tau13, to further study this important region. Using scanning alanine mutations in recombinant tau proteins, we refined the epitopes of each antibody. We examined the antibodies' relative abilities to specifically label pathological tau in non-denaturing and denaturing assays to gain insight into some of the mechanistic details of PAD exposure. We then determined the pattern of tau pathology labeled by each antibody in human hippocampal sections at various disease stages in order to characterize PAD exposure in the context of disease progression. The characteristics of reactivity for the antibodies fell into two groups. TNT1 and TNT2 recognized epitopes within amino acids 7-12 and specifically identified recombinant tau aggregates and pathological tau from Alzheimer's disease brains in a conformation-dependent manner. These antibodies labeled early pre-tangle pathology from neurons in early Braak stages and colocalized with thiazine red, a marker of fibrillar pathology, in classic neurofibrillary tangles. However, late tangles were negative for TNT1 and TNT2 indicating a loss of the epitope in later stages of tangle evolution. In contrast, Tau12 and Tau13 both identified discontinuous epitopes in the amino terminus and were unable to differentiate between normal and pathological tau in biochemical and tissue immunohistological assays. Despite the close proximity of these epitopes, the antibodies demonstrated remarkably different abilities to identify pathological

  19. First-in-man tau vaccine targeting structural determinants essential for pathological tau–tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model

    OpenAIRE

    Kontsekova, Eva; Zilka, Norbert; Kovacech, Branislav; Novak, Petr; Novak, Michal

    2014-01-01

    Introduction We have identified structural determinants on tau protein that are essential for pathological tau–tau interaction in Alzheimer’s disease (AD). These regulatory domains, revealed by monoclonal antibody DC8E8, represent a novel target for tau-directed therapy. In order to validate this target, we have developed an active vaccine, AADvac1. Methods A tau peptide encompassing the epitope revealed by DC8E8 was selected for the development of an active vaccine targeting structural deter...

  20. An Effective Neurofeedback Intervention to Improve Social Interactions in Children with Autism Spectrum Disorder

    Science.gov (United States)

    Friedrich, Elisabeth V. C.; Sivanathan, Aparajithan; Lim, Theodore; Suttie, Neil; Louchart, Sandy; Pillen, Steven; Pineda, Jaime A.

    2015-01-01

    Neurofeedback training (NFT) approaches were investigated to improve behavior, cognition and emotion regulation in children with autism spectrum disorder (ASD). Thirteen children with ASD completed pre-/post-assessments and 16 NFT-sessions. The NFT was based on a game that encouraged social interactions and provided feedback based on imitation and…

  1. Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies.

    Science.gov (United States)

    Lewis, Jada; Dickson, Dennis W

    2016-01-01

    Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles-a principle neuropathological hallmark of Alzheimer's disease (AD)-as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that

  2. Sequence variants in eukaryotic translation initiation factor 4-gamma (eIF4G1) are associated with Lewy body dementia.

    Science.gov (United States)

    Fujioka, Shinsuke; Sundal, Christina; Strongosky, Audrey J; Castanedes, Monica Case; Rademakers, Rosa; Ross, Owen A; Vilariño-Güell, Carles; Farrer, Matthew J; Wszolek, Zbigniew K; Dickson, Dennis W

    2013-03-01

    We recently reported a missense mutation and four variants in eukaryotic translation initiation factor 4-gamma (EIF4G1) associated with parkinsonism, dementia or both. In those with a positive family history, the mode of inheritance was autosomal dominant. Detailed neuropathologic descriptions of individuals with EIF4G1 genetic variants have not been reported. Herein, we report neuropathologic findings of three individuals from two American families with EIF4G1 variants. The patients had initial clinical presentations of dementia or parkinsonism and all had dementia at the time of autopsy. One family carried an EIF4G1 double variant, c.2056G>T (p.G686C) and c.3589C>T (p.R1197 W), and one family carried variant c.1505C>T (p.A502V). All three patients also carried at least one ε4 allele of apolipoprotein E. One individual presented with cognitive impairment without significant parkinsonism; one presented with memory problems followed by bradykinesia; and the third presented with cardinal signs of Parkinson's disease, followed more than a year later by cognitive dysfunction. Pathological examination showed diffuse cortical Lewy bodies and Lewy neurites in all patients. A small subset of Lewy bodies and Lewy neurites were immunopositive for eIF4G1. All patients had moderate to frequent non-neuritic, cortical amyloid plaques, mostly medial temporal neurofibrillary pathology (Braak neurofibrillary tangle stages of II to IV), and minimal or no TDP-43 pathology. The results suggest that in some patients variants in EIF4G1 can be associated with pathology that has a high likelihood of association with clinical features of dementia with Lewy bodies.

  3. Tangled up in two: a burst of genome duplications at the end of the Cretaceous and the consequences for plant evolution.

    Science.gov (United States)

    Vanneste, Kevin; Maere, Steven; Van de Peer, Yves

    2014-08-05

    Genome sequencing has demonstrated that besides frequent small-scale duplications, large-scale duplication events such as whole genome duplications (WGDs) are found on many branches of the evolutionary tree of life. Especially in the plant lineage, there is evidence for recurrent WGDs, and the ancestor of all angiosperms was in fact most likely a polyploid species. The number of WGDs found in sequenced plant genomes allows us to investigate questions about the roles of WGDs that were hitherto impossible to address. An intriguing observation is that many plant WGDs seem associated with periods of increased environmental stress and/or fluctuations, a trend that is evident for both present-day polyploids and palaeopolyploids formed around the Cretaceous-Palaeogene (K-Pg) extinction at 66 Ma. Here, we revisit the WGDs in plants that mark the K-Pg boundary, and discuss some specific examples of biological innovations and/or diversifications that may be linked to these WGDs. We review evidence for the processes that could have contributed to increased polyploid establishment at the K-Pg boundary, and discuss the implications on subsequent plant evolution in the Cenozoic.

  4. A tangled web: the challenges of implementing an evidence-based social engagement intervention for children with autism in urban public school settings.

    Science.gov (United States)

    Locke, Jill; Olsen, Anne; Wideman, Rukiya; Downey, Margaret Mary; Kretzmann, Mark; Kasari, Connie; Mandell, David S

    2015-01-01

    There is growing evidence that efficacious autism-related interventions rarely are adopted or successfully implemented in public schools, in part because of the lack of fit between the intervention and the needs and capacities of the school setting. There is little systematic information available regarding the barriers to implementation of complex interventions such as those addressing social engagement for children with autism.The present study used fieldnotes from an implementation trial to explore barriers that emerged during the training of school personnel and subsequent implementation of a social engagement intervention. A number of barriers at the individual (training) and school levels (policies surrounding recess, staffing, prioritization of competing demands, level of respect and support, and availability of resources) interfered with the continued use and sustainment of the intervention. We offer potential strategies to overcome these barriers and provide directions for future research in this critical area. Copyright © 2014. Published by Elsevier Ltd.

  5. Turnul Babel sau limbile încurcate ale naţiunilor (The Tower of Babel and the Tangled Languages of Nations

    Directory of Open Access Journals (Sweden)

    Dan PAVEL

    2013-11-01

    Full Text Available In multinational states, the quality of democracy depends on how the majority protects the rights of minorities. In post-communist Romania, there is a controversy related with the demand to recognize the Hungarian language as an official language. The author insists that before a decision is taken, Romanian citizens and decision-makers should examine carefully the status of minority languages in different parts of Europe and around the world. However, there are relevant examples of multinational states (Russia, China where minority languages are officially recognized, but democracy is far from away from consolidation. The protection of the minority rights is only a factor among others that contribute to the consolidation of democracy

  6. Tangled skeins: a first report of non-captive mating behavior in the Southeast Asian Paradise Flying Snake (Reptilia: Squamata: Colubridae: Chrysopelea paradisi

    Directory of Open Access Journals (Sweden)

    Hinrich Kaiser

    2016-02-01

    Full Text Available We describe the courtship behavior of the Paradise Flying Snake, Chrysopelea paradisi, from a series of images taken near Sandakan, eastern Sabah, Borneo, Malaysia. During the episode observed, four males moved together with a female in various states of entanglement, traveling at ground level and into a series of bushes.  The observations took place over the course of a 30-min period until the snakes were lost to view.  Our report is the first direct observation of mating behavior in C. paradisi in the wild and provides another rare glimpse of the multi-male courtship in Southeast Asian colubrids. 

  7. Tangled in the breast cancer web: an evaluation of the usage of web-based information resources by breast cancer patients.

    Science.gov (United States)

    Nguyen, Sonia Kim Anh; Ingledew, Paris-Ann

    2013-12-01

    This study describes Internet use by breast cancer patients highlighting search patterns and examining the impact of web-based information on the clinical encounter. From September 2011 to January 2012, breast cancer patients at a cancer center completed a survey. Answers were closed and open-ended. Eighty-one patients were approached and 56 completed the survey. Forty-five (80 %) respondents used the Internet and 32 (71 %) searched for breast cancer information. All used Google as their principal search engine. To evaluate quality, 47 % referred to author credentials and 41 % examined references. Most sought information with respect to treatment or prognosis. Eighty percent felt that the information increased their knowledge and influenced treatment decision making for 53 %. This study highlights search patterns and factors used by breast cancer patients in seeking web-based information. Physicians must appreciate that patients use the Internet and address discrepancies between information sought and that which is available.

  8. Ikonoklastinė polemika LDK. Vieno veikalo istorijos pinklės | Iconoclastic Controversy in the Grand Duchy of Lithuania. The Tangled Story of One Work

    Directory of Open Access Journals (Sweden)

    Ūla Ambrasaitė

    2012-01-01

    Full Text Available The article presents some introductory notes on research into the iconoclastic controversy in the Grand Duchy of Lithuania, and suggests reasons for their relevance. Writings from the early and mid-16th century which show traces of iconoclastic thought are presented. In his poem De vita et gestis Divi Hyacinthi carmen (1525, Mykolas Husovianas introduces the reader to the growing ‘Lutheran heresy’ in Western Europe, which also had an iconoclastic aspect. In the treatise by Mykolas Lietuvis De moribus Tartarorum, Lituanorum et Moscorum fragmina X, multipli historia referta (written in 1550, and printed in 1615, we can perceive not a conscious iconoclastic stance but rather a humanist criticism.A more conscious attempt to criticise the visuality of faith was made by Mikalojus Radvila Juodasis. His long letter to the papal nuncio Aloisio Lippomano (Duae epistolae, 1556 explains his intentions to form a separate Vilnius church, which would also have iconoclastic traits.The article also reviews the historiographically, but only separately, described facts about the most important work of iconoclastic polemics of the Grand Duchy of Lithuania, Andrius Volanas’ Idololatriae Loiolitarum Vilnensium oppugnatio, which was printed in 1583. The author highlights a lot of questions posed by the work, the solutions to which might allow us to judge the extent of iconoclastic thought and the importance of religious imagery in the Grand Duchy of Lithuania. By connecting the facts to a coherent narrative, the article identifies ‘blank spots’ in history, and suggests areas for further research.

  9. Teasing apart "the tangled web" of influence of policy dialogues: lessons from a case study of dialogues about healthcare reform options for Canada.

    Science.gov (United States)

    Mulvale, Gillian; McRae, Samantha A; Milicic, Sandra

    2017-07-28

    The knowledge exchange literature suggests that policy dialogues are intended to enhance short-, medium- and long-term capacities of individuals, organizations and health systems to use evidence to inform policy-making. Key features of effective dialogues have been suggested, but the linkages between these features and the realization of improved capacities for evidence-informed policy-making among dialogue attendees and the subsequent influence on policy-making activities are not well understood. We conducted a qualitative case study of a series of four policy dialogues that were convened in Canada among national, provincial and regional stakeholders on topics pertaining to healthcare financing and funding in 2011. Data sources included videos of participant perspectives captured during or immediately following each event and follow-up key informant interviews among dialogue participants held 4 years later in 2015. Three conceptual frameworks pertaining to (i) policy dialogues and capacities for evidence use, (ii) factors shaping policy-making across the policy cycle and (iii) factors shaping implementation of evidence guided the thematic analysis. We then synthesized the findings across the three frameworks. The results suggest the potential benefits of policy dialogues described in the literature were developed among the participants at these dialogues. Informants elaborated on how dialogue features influenced their capacities to use evidence, the ideas, interests and institutions during the agenda-setting and policy formulation stages of policy-making and how implementation was affected by characteristics of policy options, individuals, organizations, the external environment and processes. We present a conceptual framework that furthers our understanding of the potential influence of policy dialogues on the content and mechanisms of policy development and illustrate pathways of influence on various stages of the policy cycle from agenda setting through formulation and implementation. The framework highlights important factors for consideration in designing and evaluating policy dialogues and in supporting post-dialogue knowledge exchange efforts.

  10. In vivo tau PET imaging in dementia: Pathophysiology, radiotracer quantification, and a systematic review of clinical findings.

    Science.gov (United States)

    Hall, Benjamin; Mak, Elijah; Cervenka, Simon; Aigbirhio, Franklin I; Rowe, James B; O'Brien, John T

    2017-07-01

    In addition to the deposition of β-amyloid plaques, neurofibrillary tangles composed of aggregated hyperphosphorylated tau are one of the pathological hallmarks of Alzheimer's disease and other neurodegenerative disorders. Until now, our understanding about the natural history and topography of tau deposition has only been based on post-mortem and cerebrospinal fluid studies, and evidence continues to implicate tau as a central driver of downstream neurodegenerative processes and cognitive decline. Recently, it has become possible to assess the regional distribution and severity of tau burden in vivo with the development of novel radiotracers for positron emission tomography (PET) imaging. In this article, we provide a comprehensive discussion of tau pathophysiology, its quantification with novel PET radiotracers, as well as a systematic review of tau PET imaging in normal aging and various dementia conditions: mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, progressive supranuclear palsy, and Lewy body dementia. We discuss the main findings in relation to group differences, clinical-cognitive correlations of tau PET, and multi-modal relationships among tau PET and other pathological markers. Collectively, the small but growing literature of tau PET has yielded consistent anatomical patterns of tau accumulation that recapitulate post-mortem distribution of neurofibrillary tangles which correlate with cognitive functions and other markers of pathology. In general, AD is characterised by increased tracer retention in the inferior temporal lobe, extending into the frontal and parietal regions in more severe cases. It is also noted that the spatial topography of tau accumulation is markedly distinct to that of amyloid burden in aging and AD. Tau PET imaging has also revealed characteristic spatial patterns among various non-AD tauopathies, supporting its potential role for differential diagnosis. Finally, we propose novel directions for future

  11. Association of the apolipoprotein E {epsilon}4 allele with clinical subtypes of autopsy-confirmed Alzheimer`s Disease

    Energy Technology Data Exchange (ETDEWEB)

    Zubenko, G.S.; Stiffler, S.; Kopp, U. [Univ. of Pittsburgh School of Medicine, PA (United States)] [and others

    1994-09-15

    Consistent with previous reports, we observed a significant association of the APOE {epsilon}4 allele with Alzheimer`s Disease (AD) in a series of 91 autopsy-confirmed cases. The {epsilon}4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 {+-} 0.07), although the {epsilon}4 allele frequency in the AD cases with a negative family history (0.38 {+-} 0.05) remained significantly greater than that for the non-AD control group (0.13 {+-} 0.03). A similar increase in {epsilon}4 allele frequency (0.54 {+-} 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.35 {+-} 0.04). Contrary to previous reports, no effect of the dosage of the {epsilon}4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of {epsilon}4 and atherosclerosis, the {epsilon}4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of {epsilon}4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the {epsilon}4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an {epsilon}4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the {epsilon}4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE {epsilon}4 allele. 22 refs., 2 figs., 5 tabs.

  12. Detection of hyperphosphorylated tau protein and α-synuclein in spinal cord of patients with Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Guo YJ

    2016-02-01

    Full Text Available Yanjun Guo,1,2 Luning Wang,2 Mingwei Zhu,2 Honghong Zhang,3 Yazhuo Hu,3 Zhitao Han,3 Jia Liu,4 Weiqin Zhao,1 Dexin Wang11Department of Neurology, Beijing Friendship Hospital, Capital Medical University, 2Department of Geriatric Neurology, PLA General Hospital, 3Institute of Geriatrics, Chinese PLA General Hospital & Chinese PLA Medical Academy, 4Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaAbstract: The aim of this study was to investigate the neuropathological features of the spinal cord in patients suffering with Alzheimer’s disease (AD. Spinal cord tissue collected from three AD patients and eight controls was selected for the study. Data were collected at T2, T8, T10, L4, and S2 spinal levels. The sections were subjected to hematoxylin and eosin and Gallyas–Braak staining methods and then were immunostained with antibodies such as phosphorylated tau protein (AT8, α-synuclein, Aβ, amyloid precursor protein , ubiquitin, and TDP-43. Pathological changes exhibited by the biomarkers were detected by microscopy. Neurofibrillary tangles (NFTs were detectable in spinal anterior horn motor neurons in two of the three AD patients. AT8-positive axons or axon-like structures and AT8 expression in glial cells were detected in all three AD cases. Hyperphosphorylation of tau protein was detected in spinal anterior horn cells, glial cells, and axons, and its severity was associated with NFTs in the brain tissue. α-Synuclein-positive Lewy bodies and scattered Lewy-like neuritis were detected in the medial horn of the thoracic spinal cord and ventral sacral gray matter, respectively, in one patient who had AD with Lewy bodies. Neither amyloid deposition nor amyloid precursor protein and TDP-43 expression was detected in the spinal cord of AD patients. Spinal cord of AD patients was observed to contain phosphorylated tau protein and α-synuclein immunoreactive structures, which may play a

  13. Chronic traumatic encephalopathy in a national football league player: part II.

    Science.gov (United States)

    Omalu, Bennet I; DeKosky, Steven T; Hamilton, Ronald L; Minster, Ryan L; Kamboh, M Ilyas; Shakir, Abdulrezak M; Wecht, Cyril H

    2006-11-01

    We present the second reported case of autopsy-confirmed chronic traumatic encephalopathy in a retired professional football player, with neuropathological features that differ from those of the first reported case. These differing pathological features underscore the need for further empirical elucidation of the pathoetiology and pathological cascades of long-term neurodegenerative sequelae of professional football. A psychological autopsy was performed with the next-of-kin and wife. Medical and hospital records were reviewed. A complete autopsy was accompanied by a comprehensive forensic neuropathological examination. Restriction fragment length polymorphism analysis was performed to determine apolipoprotein-E genotype. Pertinent premortem history included a 14-year span of play in organized football starting from the age of 18 years. The subject was diagnosed with severe major depressive disorder without psychotic features after retirement, attempted suicide multiple times and finally committed suicide 12 years after retirement by ingestion of ethylene glycol. Autopsy revealed cardiomegaly, mild to moderate coronary artery disease, and evidence of acute ethylene glycol overdose. The brain showed no atrophy, a cavum septi pellucidi was present, and the substantia nigra showed mild pallor. The hippocampus and cerebellum were not atrophic. Amyloid plaques, cerebral amyloid angiopathy, and Lewy bodies were completely absent. Sparse to frequent tau-positive neurofibrillary tangles and neuropil threads were present in all regions of the brain. Tufted and thorn astrocytes, as well as astrocytic plaques, were absent. The apolipoprotein-E genotype was E3/E4. Our first and second cases both had long careers without multiple recorded concussions. Both manifested Major Depressive Disorder after retirement. Amyloid plaques were present in the first case and completely absent in the second case. Both cases exhibited neurofibrillary tangles, neuropil threads, and coronary

  14. Presence of tau pathology within foetal neural allografts in patients with Huntington's and Parkinson's disease.

    Science.gov (United States)

    Cisbani, Giulia; Maxan, Alexander; Kordower, Jeffrey H; Planel, Emmanuel; Freeman, Thomas B; Cicchetti, Francesca

    2017-11-01

    Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington's and Parkinson's disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington's and Parkinson's disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington's disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson's disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington's disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson's disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington's disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative

  15. A Unified Hypothesis of Early- and Late-Onset Alzheimer's Disease Pathogenesis.

    Science.gov (United States)

    Atwood, Craig S; Bowen, Richard L

    2015-01-01

    Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1, and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression.

  16. Biochemical assessment of precuneus and posterior cingulate gyrus in the context of brain aging and Alzheimer's disease.

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    Chera L Maarouf

    Full Text Available Defining the biochemical alterations that occur in the brain during "normal" aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1 young adult individuals, average age 26 years (n = 9; 2 middle-aged subjects, average age 59 years (n = 5; 3 oldest-old individuals, average age 93 years (n = 6. Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer's disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.

  17. Diabetes, Alzheimer disease, and vascular dementia: a population-based neuropathologic study.

    Science.gov (United States)

    Ahtiluoto, S; Polvikoski, T; Peltonen, M; Solomon, A; Tuomilehto, J; Winblad, B; Sulkava, R; Kivipelto, M

    2010-09-28

    To investigate the relation of diabetes to dementia, Alzheimer disease (AD), and vascular dementia (VaD), through analyses of incidence, mortality, and neuropathologic outcomes in a prospective population-based study of the oldest old. The Vantaa 85+ study included 553 residents living in the city of Vantaa, Finland, and aged ≥85 years on April 1, 1991. Survivors were reexamined in 1994, 1996, 1999, and 2001. Autopsies were performed in 291 persons who died during the follow-up (48% of total population). Diabetes was assessed according to self-report, medical record of physician-diagnosed diabetes, or use of antidiabetic medication. Macroscopic infarcts were identified from 1-cm coronal slices of cerebral hemispheres, 5-mm transverse brainstem slices, and sagittal cerebellum slices. Methenamine silver staining was used for β-amyloid, methenamine silver-Bodian staining for neurofibrillary tangles, and modified Bielschowsky method for neuritic plaques. Cox proportional hazards and multiple logistic regression models were used to analyze the association of diabetes with dementia and neuropathology, respectively. Diabetes at baseline doubled the incidence of dementia, AD, and VaD, and increased mortality. Individuals with diabetes were less likely to have β-amyloid (hazard ratio [HR] [95% confidence interval (CI)] was 0.48 [0.23-0.98]) and tangles (HR [95% CI] 0.72 [0.39-1.33]) but more likely to have cerebral infarcts (HR [95% CI] 1.88 [1.06-3.34]) after all adjustments. Elderly patients with diabetes develop more extensive vascular pathology, which alone or together with AD-type pathology (particularly in APOE ε4 carriers) results in increased dementia risk.

  18. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations

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    Kalback Walter M

    2008-11-01

    Full Text Available Abstract Background Mutations in the presenilin (PSEN genes are associated with early-onset familial Alzheimer's disease (FAD. Biochemical characterizations and comparisons have revealed that many PSEN mutations alter γ-secretase activity to promote accumulation of toxic Aβ42 peptides. In this study, we compared the histopathologic and biochemical profiles of ten FAD cases expressing independent PSEN mutations and determined the degradation patterns of amyloid-β precursor protein (AβPP, Notch, N-cadherin and Erb-B4 by γ-secretase. In addition, the levels of Aβ40/42 peptides were quantified by ELISA. Results We observed a wide variation in type, number and distribution of amyloid deposits and neurofibrillary tangles. Four of the ten cases examined exhibited a substantial enrichment in the relative proportions of Aβ40 over Aβ42. The AβPP N-terminal and C-terminal fragments and Tau species, assessed by Western blots and scanning densitometry, also demonstrated a wide variation. The Notch-1 intracellular domain was negligible by Western blotting in seven PSEN cases. There was significant N-cadherin and Erb-B4 peptide heterogeneity among the different PSEN mutations. Conclusion These observations imply that missense mutations in PSEN genes can alter a range of key γ-secretase activities to produce an array of subtly different biochemical, neuropathological and clinical manifestations. Beyond the broad common features of dementia, plaques and tangles, the various PSEN mutations resulted in a wide heterogeneity and complexity and differed from sporadic AD.

  19. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models.

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    Sethu Sankaranarayanan

    Full Text Available In Alzheimer's disease (AD, an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, we demonstrate that phospho-tau (p-tau antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19 led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

  20. An autopsied case of progressive supranuclear palsy presenting with cerebellar ataxia and severe cerebellar involvement.

    Science.gov (United States)

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Tatsumi, Shinsui; Mimuro, Maya; Yoshida, Mari

    2013-10-01

    A Japanese male patient presented with gait disturbance at the age of 69 years. His principal symptom was cerebellar ataxia for several years. He was initially diagnosed as having olivopontocerebellar atrophy because dysarthria and ataxia gradually developed, and head CT scan showed apparent atrophy of the cerebellum and brainstem and dilatation of the fourth ventricle. Later, he showed vertical gaze palsy, dysphagia, retrocollis, parkinsonism, axial dominant rigidity and grasp reflex, and therefore, the diagnosis was modified to progressive supranuclear palsy (PSP). Progressive atrophy of the frontotemporal lobe, cerebellum and brainstem, and dilatation of the lateral, third and fourth ventricles were evident on MRI. Gastrostomy and tracheotomy were performed 9 and 10 years after onset, respectively, and the patient died after 11 years disease duration. At autopsy the brain weighed 1000 g and showed atrophy of the frontotemporal lobe, cerebellum and brainstem. Neurofibrillary tangles, mainly globose-type revealed by Gallyas-Braak silver staining, were extensively observed in the cerebral cortex and subcortical grey matter. Numerous glial fibrillary tangles, including tuft-shaped astrocytes and coiled bodies, and extensive argyrophilic threads were also recognized, particularly in the frontal lobe, basal ganglia, cerebellar white matter, brainstem and spinal cord. The Purkinje cell layer showed severe neuron loss with Bergmann's gliosis, and the dentate nucleus showed severe neuron loss with grumose degeneration. Tau-positive/Gallyas-positive inclusions in the Purkinje cells and the glial cells of the Purkinje cell layer were observed. Pathological findings of the present patient were consistent with the diagnosis of PSP, but the olivopontocerebellar involvement, particularly in the cerebellum, was generally more severe, and the quantity of tau-positive/Gallyas-positive structures were more abundant than in typical PSP cases. The existence of a distinct, rare PSP

  1. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology.

    Science.gov (United States)

    Perez-Nievas, Beatriz G; Stein, Thor D; Tai, Hwan-Ching; Dols-Icardo, Oriol; Scotton, Thomas C; Barroeta-Espar, Isabel; Fernandez-Carballo, Leticia; de Munain, Estibaliz Lopez; Perez, Jesus; Marquie, Marta; Serrano-Pozo, Alberto; Frosch, Mathew P; Lowe, Val; Parisi, Joseph E; Petersen, Ronald C; Ikonomovic, Milos D; López, Oscar L; Klunk, William; Hyman, Bradley T; Gómez-Isla, Teresa

    2013-08-01

    Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in

  2. Decreased presence of perforated synapses in a triple-transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Bertoni-Freddari, Carlo; Sensi, Stefano L; Giorgetti, Belinda; Balietti, Marta; Di Stefano, Giuseppina; Canzoniero, Lorella M T; Casoli, Tiziana; Fattoretti, Patrizia

    2008-04-01

    Transgenic mouse models of Alzheimer's disease (AD) are useful tools to further our understanding of AD genotype-phenotype interaction. The triple transgenic mice harboring mutant forms of APP/PS1/Tau (3xTg-AD) exhibit beta-amyloid (Abeta) plaques (by 6 months of age) as well as neurofibrillary tangles (by 10-12 months of age). In this study, we characterized morphological alterations of hippocampal synapses obtained from 13-month-old 3xTg-AD and age-matched control (PS1-KI) mice. Numeric density of synapses (Nv, number of junctions/microm(3) of tissue), average synaptic contact area (S), and synaptic surface density (Sv, total synaptic contact area/microm(3) of tissue) were investigated by morphometric methods in the AD vulnerable CA1 pyramidal cell layer. Comparisons between 3xTg-AD and control mice showed no statistically significant differences in any of the three parameters; however, a significant decrease (by 28.5%) in the fraction of perforated junctional areas (PS) was observed in the 3xTg-AD mice. As PS is a reliably indirect index of synaptic plasticity, a decreased PS number might represent a subtle and early sign of synaptic dysfunction occurring in the 3xTg-AD mice, and lend support to the hypothesis that altered synaptic function is a critical feature of AD.

  3. Can oral infection be a risk factor for Alzheimer's disease?

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    Ingar Olsen

    2015-09-01

    Full Text Available Alzheimer's disease (AD is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species, viruses (herpes simplex type I, and yeasts (Candida species. A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible etiology of late-onset AD (LOAD.

  4. In vivo functional brain mapping in a conditional mouse model of human tauopathy (taup301l reveals reduced neural activity in memory formation structures

    Directory of Open Access Journals (Sweden)

    Perez Pablo D

    2013-02-01

    Full Text Available Abstract Background Tauopathies are characterized by intracellular deposition of the microtubule-associated protein tau as filamentous aggregates. The rTg4510 mouse conditionally expresses mutant human tau protein in various forebrain areas under the Tet-off expression system. Mice develop neurofibrillary tangles, with significant neuronal loss and cognitive deficits by 6 months of age. Previous behavioral and biochemical work has linked the expression and aggregates of mutant tau to functional impairments. The present work used manganese-enhanced magnetic resonance imaging (MEMRI to investigate basal levels of brain activity in the rTg4510 and control mice. Results Our results show an unmistakable curtailment of neural activity in the amygdala and hippocampus, two regions known for their role in memory formation, but not the cortex, cerebellum, striatum and hypothalamus in tau expressing mice. Conclusion Behavioral impairments associated with changes in activity in these areas may correspond to age progressive mutant tauP301L-induced neurodegeneration.

  5. Neuropathological correlates of late-life depression in older people.

    Science.gov (United States)

    Tsopelas, Christos; Stewart, Robert; Savva, George M; Brayne, Carol; Ince, Paul; Thomas, Alan; Matthews, Fiona E

    2011-02-01

    Depression is common in old age and is associated with risk of dementia, but its neuropathological correlates in the community are unknown. To investigate for the first time in a population-representative sample of people with no dementia the association between depression observed during life and neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, brain atrophy and cerebrovascular disease found in the brain at post-mortem. Out of 456 donations to a population-based study, 153 brains were selected where donors had no dementia measured in life. Alzheimer and vascular pathology measures, Lewy bodies and neuronal loss were compared between those with (n = 36) and without (n = 117) depression ascertained using a fully structured diagnostic interview during life. Brain areas examined included frontal, parietal, temporal and occipital cortical areas as well as the entorhinal cortex, hippocampus and brain-stem monoaminergic nuclei. Depression was significantly associated with the presence of subcortical Lewy bodies. No association was found between depression and cerebrovascular or Alzheimer pathology in cortical or subcortical areas, although depression was associated with neuronal loss in the hippocampus as well as in some of the subcortical structures investigated (nucleus basalis, substantia nigra, raphe nucleus). Late-life depression was associated with subcortical and hippocampal neuronal loss but not with cerebrovascular or Alzheimer pathology.

  6. Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer's disease.

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    Patricia F Kao

    2010-10-01

    Full Text Available During the progression of Alzheimer's disease (AD, hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF receptor tyrosine kinase B (TrkB, mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.

  7. Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

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    Md. Sahab Uddin

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ, and neurofibrillary tangles (NFTs, composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

  8. Implications of Neuroimmunity in Alzheimer’s Disease: A Review

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    Katriel Lee

    2017-10-01

    Full Text Available AD is characterized cognitively by memory, problem-solving, and language difficulties. It is estimated that 5.4 million Americans currently have Alzheimer’s disease (AD. The cognitive difficulties in AD are reflected in the brain through the accumulation of amyloid-β (Aβ in cerebral amyloid angiopathy (CAA, neurofibrillary tau tangles, neuronal tissue atrophy, and neuroinflammation, but the exact cause of AD is still in question. However, evidence suggests that differences in neuroimmune function—the central nervous system’s ability to resist disease—may play a role in the development and progression of AD. This paper largely relates neuroimmune changes to the amyloid hypothesis of AD. This approach relates AD to Aβ production and clearance, and therefore, targets Aβ for treatment uses. A thorough literature search revealed evidence that the blood-brain barrier (BBB, glial cell mediation and effects on neuroinflammation, and cerebrospinal fluid (CSF and interstitial fluid (ISF drainage systems are changed in AD. These changes seem to be detrimental for the AD brain and Aβ accumulation. Future research should be conducted regarding characterization of the lymphatic system in the human dura, the balance of helpful and harmful effects of activated microglia, the driving forces of paravascular CSF-ISF exchange, the effects of sleep on neuroimmunity, and genetic risk factors for neuroimmune dysfunction.

  9. Diabetes mellitus accelerates Aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates.

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    Sachi Okabayashi

    Full Text Available Growing evidence suggests that diabetes mellitus (DM is one of the strongest risk factors for developing Alzheimer's disease (AD. However, it remains unclear why DM accelerates AD pathology. In cynomolgus monkeys older than 25 years, senile plaques (SPs are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. In laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 DM. In the present study, we performed histopathological and biochemical analyses of brain tissue in cynomolgus monkeys with type 2 DM to clarify the relationship between DM and AD pathology. Here, we provide the evidence that DM accelerates Aβ pathology in vivo in nonhuman primates who had not undergone any genetic manipulation. In DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices, even in monkeys younger than 20 years. Biochemical analyses of brain revealed that the amount of GM1-ganglioside-bound Aβ (GAβ--the endogenous seed for Aβ fibril formation in the brain--was clearly elevated in DM-affected monkeys. Furthermore, the level of Rab GTPases was also significantly increased in the brains of adult monkeys with DM, almost to the same levels as in aged monkeys. Intraneuronal accumulation of enlarged endosomes was also observed in DM-affected monkeys, suggesting that exacerbated endocytic disturbance may underlie the acceleration of Aβ pathology due to DM.

  10. Application of neurite orientation dispersion and density imaging (NODDI) to a tau pathology model of Alzheimer's disease.

    LENUS (Irish Health Repository)

    Colgan, N

    2015-10-23

    Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer\\'s disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer\\'s disease.

  11. Amyloid-β precursor protein facilitates the regulator of calcineurin 1-mediated apoptosis by downregulating proteasome subunit α type-5 and proteasome subunit β type-7.

    Science.gov (United States)

    Wu, Yili; Deng, Yu; Zhang, Shuting; Luo, Yawen; Cai, Fang; Zhang, Zhuohua; Zhou, Weihui; Li, Tingyu; Song, Weihong

    2015-01-01

    Individuals with Down syndrome (DS), caused by trisomy of chromosome 21, inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques, neurofibrillary tangles, and neuronal loss. Amyloid-β protein, the major component of neuritic plaques, is the proteolytic product of amyloid-β precursor protein (APP). APP and the regulator of calcineurin 1 (RCAN1) genes on chromosome 21 play a pivotal role in promoting plaque formation and neuronal apoptosis. However, the mechanism underlying AD pathogenesis in DS is not well defined. In this study, we demonstrated that APP significantly increased RCAN1 level in both cells and transgenic mice. Overexpression of APP significantly reduced the expression of 2 proteasome subunits, proteasome subunit α type-5 and proteasome subunit β type-7, leading to the inhibition of proteasomal degradation of RCAN1. Furthermore, knockdown of RCAN1 expression attenuated APP-induced neuronal apoptosis. Taken together, the results clearly showed that APP has a previously unknown function in regulating RCAN1-mediated neuronal apoptosis through the proteasome pathway. Our study demonstrates a novel mechanism by which overexpression of APP and RCAN1 causes neurodegeneration and AD pathogenesis in DS, and it provides new insights into the potential of targeting APP-induced proteasomal impairment and RCAN1 accumulation for AD and DS treatment. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation*

    Science.gov (United States)

    Sun, Xiulian; Wu, Yili; Chen, Bin; Zhang, Zhuohua; Zhou, Weihui; Tong, Yigang; Yuan, Junying; Xia, Kun; Gronemeyer, Hinrich; Flavell, Richard A.; Song, Weihong

    2011-01-01

    Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3−/− neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress- and Aβ-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS. PMID:21216952

  13. Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase-3 activation.

    Science.gov (United States)

    Sun, Xiulian; Wu, Yili; Chen, Bin; Zhang, Zhuohua; Zhou, Weihui; Tong, Yigang; Yuan, Junying; Xia, Kun; Gronemeyer, Hinrich; Flavell, Richard A; Song, Weihong

    2011-03-18

    Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3(-/-) neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress- and Aβ-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS.

  14. Analyzing Microarray Data of Alzheimer's Using Cluster Analysis to Identify the Biomarker Genes

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    Satya vani Guttula

    2012-01-01

    Full Text Available Alzheimer is characterized by the presence of senile plaques and neurofibrillary tangles in cortical regions of the brain. The experimental data is taken from Gene Expression Omnibus. A hierarchical Cluster analysis and TreeView were performed to group genes on the basis of the expression pattern. The dynamic change of expression over time and diverse patterns of expression support the concept of a complex local milieu. TreeView allows the organized data to be visualized. List of 24 genes were obtained which showed high expression levels. Three genes, SORL1, APP, and APOE, are suspected to cause Alzheimer’s whereas the other 21 genes are related to other diseases but may also be found to be associated with Alzheimer’s, and these are TMEM59, CCT4, IGF2R, SFPQ, PRDX3, RNF14, IDS, SSBP1, SYNE2, TXNL4A, STXBP3, SMARCB1, ULK2, AGTPBP1, FABP7, CALB1, H2AFY, COPA, SAP18, ATIC and SYNCRIP.

  15. Alzheimer's disease, oestrogen and mitochondria: an ambiguous relationship.

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    Grimm, Amandine; Lim, Yun-An; Mensah-Nyagan, Ayikoe Guy; Götz, Jürgen; Eckert, Anne

    2012-08-01

    Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ- and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ-ABAD interaction.

  16. Insulin as a bridge between type 2 diabetes and Alzheimer disease – How anti-diabetics could be a solution for dementia

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    Inês eSebastião

    2014-07-01

    Full Text Available Type 2 diabetes (T2D and Alzheimer disease (AD are two major health issues nowadays. T2D is an ever increasing epidemic, affecting millions of elderly people worldwide, with major repercussions in the patients’ daily life. This is mostly due to its chronic complications that may affect brain and constitutes a risk factor for AD. T2D principal hallmark is insulin resistance which also occurs in AD, rendering both pathologies more than mere unrelated diseases. This hypothesis has been reinforced in the recent years, with a high number of studies highlighting the existence of several common molecular links. As such, it is not surprising that AD has been considered as the type 3 diabetes or a brain-specific T2D, supporting the idea that a beneficial therapeutic strategy against T2D might be also beneficial against AD. Herewith, we aim to review some of the recent developments on the common features between T2D and AD, namely on insulin signaling and its participation in the regulation of amyloid  (Aβ plaque and neurofibrillary tangle formation (the two major neuropathological hallmarks of AD. We also critically analyze the promising field that some anti-T2D drugs may protect against dementia and AD, with a special emphasis on the novel incretin/glucagon-like peptide-1 receptor agonists.

  17. The rise and fall of insulin signaling in Alzheimer's disease.

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    Chami, B; Steel, A J; De La Monte, S M; Sutherland, Greg T

    2016-06-01

    The prevalence of both diabetes and Alzheimer's disease (AD) are reaching epidemic proportions worldwide. Alarmingly, diabetes is also a risk factor for Alzheimer's disease. The AD brain is characterised by the accumulation of peptides called Aβ as plaques in the neuropil and hyperphosphorylated tau protein in the form of neurofibrillary tangles within neurons. How diabetes confers risk is unknown but a simple linear relationship has been proposed whereby the hyperinsulinemia associated with type 2 diabetes leads to decreased insulin signaling in the brain, with downregulation of the PI3K/AKT signalling pathway and its inhibition of the major tau kinase, glycogen synthase kinase 3β. The earliest studies of post mortem AD brain tissue largely confirmed this cascade of events but subsequent studies have generally found either an upregulation of AKT activity, or that the relationship between insulin signaling and AD is independent of glycogen synthase kinase 3β altogether. Given the lack of success of beta-amyloid-reducing therapies in clinical trials, there is intense interest in finding alternative or adjunctive therapeutic targets for AD. Insulin signaling is a neuroprotective pathway and represents an attractive therapeutic option. However, this incredibly complex signaling pathway is not fully understood in the human brain and particularly in the context of AD. Here, we review the ups and downs of the research efforts aimed at understanding how diabetes modifies AD risk.

  18. Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer's disease

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    Ciavardelli, D; Silvestri, E; Viscovo, A Del; Bomba, M; Gregorio, D De; Moreno, M; Ilio, C Di; Goglia, F; Canzoniero, L M T; Sensi, S L

    2010-01-01

    The triple-transgenic Alzheimer (3 × Tg-AD) mouse expresses mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develops plaques and neurofibrillary tangles with a temporal- and region-specific profile that resembles the neuropathological progression of Alzheimer's disease (AD). In this study, we used proteomic approaches such as two-dimensional gel electrophoresis and mass spectrometry to investigate the alterations in protein expression occurring in the brain and cerebellum of 3 × Tg-AD and presenilin-1 (PS1) knock-in mice (animals that do not develop Aβ- or tau-dependent pathology nor cognitive decline and were used as control). Finally, using the Ingenuity Pathway Analysis we evaluated novel networks and molecular pathways involved in this AD model. We identified several differentially expressed spots and analysis of 3 × Tg-AD brains showed a significant downregulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release, as well as a set of proteins that are associated with cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an upregulation of proteins involved in carbohydrate metabolism and protein catabolism. Our findings help to unravel the pathogenic brain mechanisms set in motion by mutant amyloid precursor protein (APP) and hyperphosphorylated tau. These data also reveal cerebellar pathways that may be important to counteract the pathogenic actions of Aβ and tau, and ultimately offer novel targets for therapeutic intervention. PMID:21368863

  19. Cerebrospinal Fluid Biomarkers for Differentiation of Frontotemporal Lobar Degeneration from Alzheimer’s Disease

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    David J Irwin

    2013-02-01

    Full Text Available Accurate ante mortem diagnosis in frontotemporal lobar degeneration (FTLD is crucial to the development and implementation of etiology-based therapies. Several neurodegenerative disease-associated proteins, including the major protein constituents of inclusions in Alzheimer’s disease (AD associated with amyloid-beta (Aβ1-42 plaque and tau neurofibrillary tangle pathology, can be measured in cerebrospinal fluid (CSF for diagnostic applications. Comparative studies using autopsy-confirmed samples suggest that CSF total-tau (t-tau and Aβ1-42 levels can accurately distinguish FTLD from AD, with a high t-tau to Aβ1-42 ratio diagnostic of AD; however, there is also an urgent need for FTLD-specific biomarkers. These analytes will require validation in large autopsy-confirmed cohorts and face challenges of standardization of within- and between-laboratory sources of error. In addition, CSF biomarkers with prognostic utility and longitudinal study of CSF biomarker levels over the course of disease are also needed. Current goals in the field include identification of analytes that are easily and reliably measured and can be used alone or in a multi-modal approach to provide an accurate prediction of underlying neuropathology for use in clinical trials of disease modifying treatments in FTLD. To achieve these goals it will be of the utmost importance to view neurodegenerative disease, including FTLD, as a clinicopathological entity, rather than exclusively a clinical syndrome.

  20. Epigenetic modification is linked to Alzheimer's disease: is it a maker or a marker?

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    Lee, Junghee; Ryu, Hoon

    2010-10-01

    Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder and shows progressive memory loss and cognitive decline. Intraneuronal filaments composed of aggregated hyperphosphorylated tau protein, called neurofibrillary tangles, along with extracellular accumulations of amyloid ß protein (Aß), called senile plaques, are known to be the neuropathological hallmarks of AD. In light of recent studies, epigenetic modification has emerged as one of the pathogenic mechanisms of AD. Epigenetic changes encompass an array of molecular modifications to both DNA and chromatin, including transcription factors and cofactors. In this review, we summarize how DNA methylation and changes to DNA chromatin packaging by post-translational histone modification are involved in AD. In addition, we describe the role of SIRTs, histone deacetylases, and the effect of SIRT-modulating drugs on AD. Lastly, we discuss how amyloid precursor protein (APP) intracellular domain (AICD) regulates neuronal transcription. Our understanding of the epigenomes and transcriptomes of AD may warrant future identification of novel biological markers and beneficial therapeutic targets for AD.

  1. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

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    Matthew Furgerson

    Full Text Available The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58 enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  2. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

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    Furgerson, Matthew; Fechheimer, Marcus; Furukawa, Ruth

    2012-01-01

    The main pathological hallmarks of Alzheimer's disease are amyloid-beta plaques and neurofibrillary tangles, which are primarily composed of amyloid precursor protein (APP) and tau, respectively. These proteins and their role in the mechanism of neurodegeneration have been extensively studied. Hirano bodies are a frequently occurring pathology in Alzheimer's disease as well as other neurodegenerative diseases. However, the physiological role of Hirano bodies in neurodegenerative diseases has yet to be determined. We have established cell culture models to study the role of Hirano bodies in amyloid precursor protein and tau-induced cell death mechanisms. Exogenous expression of APP and either of its c-terminal fragments c31 or Amyloid Precursor Protein Intracellular Domain c58 (AICDc58) enhance cell death. The presence of tau is not required for this enhanced cell death. However, the addition of a hyperphosphorylated tau mimic 352PHPtau significantly increases cell death in the presence of both APP and c31 or AICDc58 alone. The mechanism of cell death induced by APP and its c-terminal fragments and tau was investigated. Fe65, Tip60, p53, and caspases play a role in tau-independent and tau-dependent cell death. In addition, apoptosis was determined to contribute to cell death. The presence of model Hirano bodies protected against cell death, indicating Hirano bodies may play a protective role in neurodegeneration.

  3. The 2,6-disubstituted naphthalene derivative FDDNP labeling reliably predicts Congo red birefringence of protein deposits in brain sections of selected human neurodegenerative diseases.

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    Smid, Lojze M; Vovko, Tomaz D; Popovic, Mara; Petric, Andrej; Kepe, Vladimir; Barrio, Jorge R; Vidmar, Gaj; Bresjanac, Mara

    2006-04-01

    Deposition of conformationally altered proteins prominently characterizes pathogenesis and pathomorphology of a number of neurodegenerative disorders. 2-(1-{6-[(2-[F-18]fluoroethyl) (methyl)amino]-2-naphthyl} ethylidene) malononitrile ([F-18]FDDNP), a hydrophobic, viscosity-sensitive, solvent-sensitive, fluorescent imaging probe has been used with positron emission tomography to visualize brain pathology in the living brain of Alzheimer disease (AD) patients. Its non-radiofluorinated analog FDDNP was shown to label senile plaques and neurofibrillary tangles (NFTs) in brain tissue sections. This work aimed at evaluating FDDNP labeling of various protein deposits in fixed, paraffin-embedded brain tissue sections of selected neurodegenerative disorders: AD, cerebral amyloid angiopathy (CAA), transmissible spongiform encephalopathies, progressive supranuclear palsy (PSP), Pick disease (PiD), Parkinson disease, dementia with Lewy bodies, multiple system atrophy (MSA). Cerebral hypertensive vascular hyalinosis (HVH) was used as negative control. Significant agreement between amyloid histochemical properties and FDDNP labeling of the deposits was established. FDDNP labeling showed high positive predictive value for birefringence in senile plaques and NFTs in AD, prion plaques and amyloid deposits in CAA. No FDDNP labeled structures were observed in HVH, PSP, PiD or MSA tissue sections. Our findings may be of significant value for the detection of neuropathological aggregates with [F-18]FDDNP in some of these disorders in the living brain of human subjects.

  4. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia.

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    Gold, Gabriel; Kövari, Enikö; Herrmann, François R; Canuto, Alessandra; Hof, Patrick R; Michel, Jean-Pierre; Bouras, Constantin; Giannakopoulos, Panteleimon

    2005-06-01

    Most previous studies addressed the cognitive impact of lacunar infarcts using radiologic correlations that are known to correlate poorly with neuropathological data. Moreover, absence of systematic bilateral assessment of vascular lesions and masking effects of Alzheimer disease pathology and macrovascular lesions may explain discrepancies among previous reports. To define the relative contribution of silent lacunes to cognitive decline, we performed a detailed analysis of lacunar and microvascular pathology in both cortical and subcortical areas of 72 elderly individuals without significant neurofibrillary tangle pathology or macrovascular lesions. Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral assessment of microvascular ischemic pathology and lacunes; statistical analysis included multivariate models controlling for age, amyloid deposits, and microvascular pathology. Thalamic and basal ganglia lacunes were negatively associated with CDR scores; cortical microinfarcts, periventricular and diffuse white matter demyelination also significantly affected cognition. In a multivariate model, cortical microinfarcts and thalamic and basal ganglia lacunes explained 22% of CDR variability; amyloid deposits and microvascular pathology explained 12%, and the assessment of thalamic and basal ganglia lacunes added an extra 17%. Deep white matter lacunes were not related to cognitive status in univariate and multivariate models. In agreement with the recently proposed concept of subcortical ischemic vascular dementia, our autopsy series provides important evidence that gray matter lacunes are independent predictors of cognitive decline in elderly individuals without concomitant dementing processes such as Alzheimer disease.

  5. Modeling the complex pathology of Alzheimer’s disease in Drosophila

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    Fernandez-Funez, Pedro; de Mena, Lorena; Rincon-Limas, Diego E.

    2015-01-01

    Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. PMID:26024860

  6. Melatonin in Alzheimer’s Disease

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    Jian-Zhi Wang

    2013-07-01

    Full Text Available Alzheimer’s disease (AD, an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP of aggregated β-amyloid (Aβ and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD.

  7. REM sleep behavior disorder and neuropathology in Parkinson's disease.

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    Postuma, Ronald B; Adler, Charles H; Dugger, Brittany N; Hentz, Joseph G; Shill, Holly A; Driver-Dunckley, Erika; Sabbagh, Marwan N; Jacobson, Sandra A; Belden, Christine M; Sue, Lucia I; Serrano, Geidy; Beach, Thomas G

    2015-09-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with differences in clinical phenotype, including dementia, autonomic loss, and gait dysfunction. The pathological basis for this remains unclear. Parkinson's disease subjects in a longitudinal clinicopathologic study were screened for probable RBD with the Mayo Sleep Questionnaire. After death, semiquantitative analyses were conducted for synuclein, amyloid, neurofibrillary tangles, and cerebrovascular lesions. Forty cases had probable RBD (PD+RBD), and 41 did not (PD-RBD). Despite similar age at death (∼80 y) and disease duration (∼14.5 y), PD+RBD had increased synuclein deposition in all regions examined, with nine of 10 regions significantly different. The Lewy body 10-region total score (scale = 0-40) was 29.5 in PD+RBD versus 24.5 in PD-RBD (Cohen-d effect size = 0.79, P = 0.002). Cerebrovascular lesion burden was slightly higher in PD-RBD. Although overlap occurs between groups, PD patients with probable RBD may have greater density and range of synuclein pathology on autopsy. © 2015 International Parkinson and Movement Disorder Society.

  8. Long and short-term CDK5 knockdown prevents spatial memory dysfunction and tau pathology of triple transgenic Alzheimer´s mice

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    John Fredy Castro-Alvarez

    2014-09-01

    Full Text Available CDK5 is a member of the cyclin-dependent kinase family with diverse functions in both the developing and mature nervous system. The inappropriate activation of CDK5 due to the proteolytic release of the activator fragment p25 from the membrane contributes to the formation of neurofibrillary tangles and chronic neurodegeneration. At 18 months of age 3xTg-AD mice were sacrificed after one year (long term or three weeks (short term of CDK5 knockdown. In long-term animals CDK5 knockdown prevented insoluble Tau formation in the hippocampi and prevented spatial memory impairment. In short-term animals, CDK5 knockdown showed reduction of CDK5, reversed Tau aggregation, and improved spatial memory compared to scrambled treated old 3xTg-AD mice. Neither long-term nor short-term CDK5 knock-down had an effect on old littermates. These findings further validate CDK5 as a target for Alzheimer’s disease both as a preventive measure and after the onset of symptoms.

  9. Mutation in archain 1, a subunit of COPI coatomer complex, causes diluted coat color and Purkinje cell degeneration.

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    Xinjie Xu

    2010-05-01

    Full Text Available Intracellular trafficking is critical for delivering molecules and organelles to their proper destinations to carry out normal cellular functions. Disruption of intracellular trafficking has been implicated in the pathogenesis of various neurodegenerative disorders. In addition, a number of genes involved in vesicle/organelle trafficking are also essential for pigmentation, and loss of those genes is often associated with mouse coat-color dilution and human hypopigmentary disorders. Hence, we postulated that screening for mouse mutants with both neurological defects and coat-color dilution will help identify additional factors associated with intracellular trafficking in neuronal cells. In this study, we characterized a mouse mutant with a unique N-ethyl-N-nitrosourea (ENU-induced mutation, named nur17. nur17 mutant mice exhibit both coat-color dilution and ataxia due to Purkinje cell degeneration in the cerebellum. By positional cloning, we identified that the nur17 mouse carries a T-to-C missense mutation in archain 1 (Arcn1 gene which encodes the delta subunit of the coat protein I (COPI complex required for intracellular trafficking. Consistent with this function, we found that intracellular trafficking is disrupted in nur17 melanocytes. Moreover, the nur17 mutation leads to common characteristics of neurodegenerative disorders such as abnormal protein accumulation, ER stress, and neurofibrillary tangles. Our study documents for the first time the physiological consequences of the impairment of the ARCN1 function in the whole animal and demonstrates a direct association between ARCN1 and neurodegeneration.

  10. Spatially pathogenic forms of tau detected in Alzheimer's disease brain tissue by fluorescence lifetime-based Förster resonance energy transfer.

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    Larionov, Sergey; Wielgat, Przemyslaw; Wang, Yiner; Thal, Dietmar Rudolf; Neumann, Harald

    2010-09-30

    In tauopathies including Alzheimer's disease (AD) tau molecules have lost their normal spatial distance to each other and appear in oligomeric or aggregated forms. Conventional immunostaining methods allow detection of abnormally phosphorylated or conformationally altered aggregated tau proteins, but fail to visualize oligomeric forms of tau. Here we show that tau molecules that lost their normal spatial localization can be detected on a subcellular level in postmortem central nervous system (CNS) tissue sections of AD patients by fluorescence lifetime-based Förster resonance energy transfer (FRET). Paraffin sections were co-immunostained with two tau-specific monoclonal antibodies recognizing the same epitope, but labeled with distinct fluorescence dyes suitable for spatial resolution at a nanometer scale by lifetime-based FRET. A FRET signal was detected in neuritic plaques and neurofibrillary tangles of CNS tissue sections of AD patients, showing associated tau proteins typically reflecting either fibrillary, oligomeric or aggregated tau. The 'pretangle-like' structures within the neuronal perikarya did not contain spatially pathogenic forms of tau accordingly to this method. Data demonstrate that fluorescence lifetime-based FRET can be applied to human brain tissue sections to detect pathogenic forms of tau molecules that lost their normal spatial distance. Copyright 2010 Elsevier B.V. All rights reserved.

  11. An update on the toxicity of Aβ in Alzheimer’s disease

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    Jürgen Götz

    2008-12-01

    Full Text Available Jürgen Götz1, Lars M Ittner1, Nicole Schonrock1, Roberto Cappai21Alzheimer’s and Parkinson’s Disease Laboratory, Brain and Mind Research Institute, University of Sydney, NSW, Australia; 2Department of Pathology, The University of Melbourne, Victoria, AustraliaAbstract: Alzheimer’s disease is characterized histopathologically by deposition of insoluble forms of the peptide Aβ and the protein tau in brain. Aβ is the principal component of amyloid plaques and tau of neurofibrillary tangles. Familial cases of AD are associated with causal mutations in the gene encoding the amyloid precursor protein, APP, from which the amyloidogenic Aβ peptide is derived, and this supports a role for Aβ in disease. Aβ can promote tau pathology and at the same time its toxicity is also tau-dependent. Aβ can adopt different conformations including soluble oligomers and insoluble fibrillar species present in plaques. We discuss which of these conformations exert toxicity, highlight molecular pathways involved and discuss what has been learned by applying functional genomics.Keywords: amyloid, mitochondria, oligomer, proteomic, tau, transgenic

  12. GBA mutations in Parkinson disease: earlier death but similar neuropathological features.

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    Adler, C H; Beach, T G; Shill, H A; Caviness, J N; Driver-Dunckley, E; Sabbagh, M N; Patel, A; Sue, L I; Serrano, G; Jacobson, S A; Davis, K; Belden, C M; Dugger, B N; Paciga, S A; Winslow, A R; Hirst, W D; Hentz, J G

    2017-11-01

    Mutations in the glucocerebrosidase (GBA) gene are known to be a risk factor for Parkinson's disease (PD). Data on clinicopathological correlation are limited. The purpose of this study was to determine the clinicopathological findings that might distinguish PD cases with and without mutations in the GBA gene. Data from the Arizona Study of Aging and Neurodegenerative Disorders were used to identify autopsied PD cases that did or did not have a GBA gene mutation. Clinical and neuropathological data were compared. Twelve PD cases had a GBA mutation and 102 did not. The GBA mutation cases died younger (76 vs. 81 years of age) but there was no difference in disease duration or clinical examination findings. No neuropathological differences were found in total or regional semi-quantitative scores for Lewy-type synucleinopathy, senile plaques, neurofibrillary tangles, white matter rarefaction or cerebral amyloid angiopathy scores. In longitudinally assessed, autopsied PD cases, those with GBA mutations had a younger age at death but there was no evidence for clinical or neuropathological differences compared to cases without GBA mutations. Due to the small GBA group size, small differences cannot be excluded. © 2017 EAN.

  13. Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer's disease.

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    Braidy, Nady; Essa, Musthafa Mohamed; Poljak, Anne; Selvaraju, Subash; Al-Adawi, Samir; Manivasagm, Thamilarasan; Thenmozhi, Arokiasamy Justin; Ooi, Lezanne; Sachdev, Perminder; Guillemin, Gilles J

    2016-10-04

    Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by extracellular plaques containing abnormal Amyloid Beta (Aβ) aggregates, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, microglia-dominated neuroinflammation, and impairments in synaptic plasticity underlying cognitive deficits. Therapeutic strategies for the treatment of AD are currently limited. In this study, we investigated the effects of dietary supplementation of 4% pomegranate extract to a standard chow diet on neuroinflammation, and synaptic plasticity in APPsw/Tg2576 mice brain. Treatment with a custom mixed diet (pellets) containing 4% pomegranate for 15 months ameliorated the loss of synaptic structure proteins, namely PSD-95, Munc18-1, and SNAP25, synaptophysin, phosphorylation of Calcium/Calmodulin Dependent Protein Kinase IIα (p-CaMKIIα/ CaMKIIα), and phosphorylation of Cyclic AMP-Response Element Binding Protein (pCREB/CREB), inhibited neuroinflammatory activity, and enhanced autophagy, and activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway. These neuroprotective effects were associated with reduced β-site cleavage of Amyloid Precursor Protein in APPsw/Tg2576 mice. Therefore, long-term supplementation with pomegranates can attenuate AD pathology by reducing inflammation, and altering APP-dependent processes.

  14. Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA).

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    Mikolaenko, Irina; Pletnikova, Olga; Kawas, Claudia H; O'Brien, Richard; Resnick, Susan M; Crain, Barbara; Troncoso, Juan C

    2005-02-01

    Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.

  15. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions.

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    Wilhelmus, Micha M M; van der Pol, Susanne M A; Jansen, Quentin; Witte, Maarten E; van der Valk, Paul; Rozemuller, Annemieke J M; Drukarch, Benjamin; de Vries, Helga E; Van Horssen, Jack

    2011-02-01

    Mitochondrial dysfunction and oxidative stress are hallmarks of various neurological disorders, including multiple sclerosis (MS), Alzheimer disease (AD), and Parkinson disease (PD). Mutations in PINK1, a mitochondrial kinase, have been linked to the occurrence of early onset parkinsonism. Currently, various studies support the notion of a neuroprotective role for PINK1, as it protects cells from stress-mediated mitochondrial dysfunction, oxidative stress, and apoptosis. Because information about the distribution pattern of PINK1 in neurological diseases other than PD is scarce, we here investigated PINK1 expression in well-characterized brain samples derived from MS and AD individuals using immunohistochemistry. In control gray matter PINK1 immunoreactivity was observed in neurons, particularly neurons in layers IV-VI. Astrocytes were the most prominent cell type decorated by anti-PINK1 antibody in the white matter. In addition, PINK1 staining was observed in the cerebrovasculature. In AD, PINK1 was found to colocalize with classic senile plaques and vascular amyloid depositions, as well as reactive astrocytes associated with the characteristic AD lesions. Interestingly, PINK1 was absent from neurofibrillary tangles. In active demyelinating MS lesions we observed a marked astrocytic PINK1 immunostaining, whereas astrocytes in chronic lesions were weakly stained. Taken together, we observed PINK1 immunostaining in both AD and MS lesions, predominantly in reactive astrocytes associated with these lesions, suggesting that the increase in astrocytic PINK1 protein might be an intrinsic protective mechanism to limit cellular injury. Copyright © 2010 Elsevier Inc. All rights reserved.

  16. Aluminum in the diet and Alzheimer's disease: from current epidemiology to possible disease-modifying treatment.

    Science.gov (United States)

    Frisardi, Vincenza; Solfrizzi, Vincenzo; Capurso, Cristiano; Kehoe, Patrick G; Imbimbo, Bruno P; Santamato, Andrea; Dellegrazie, Flora; Seripa, Davide; Pilotto, Alberto; Capurso, Antonio; Panza, Francesco

    2010-01-01

    In recent years, interest in the potential role of metals in the pathogenesis of Alzheimer's disease (AD) has grown considerably. In particular, aluminum (Al) neurotoxicity was suggested after its discovery in the senile plaques and neurofibrillary tangles that represent the principal neuropathological hallmarks of AD. Al is omnipresent in everyday life and can enter the human body from several sources, most notably from drinking water and food consumption. The evidence supporting association from ingestion of Al from drinking water is somewhat stronger than for its ingestion from food. However, other elements present in drinking water, such as fluoride, copper, zinc, or iron could also have an effect on cognitive impairment or modify any Al neurotoxicity. Some epidemiological studies, but not all, suggested that silica could be protective against Al damage, because it reduces oral absorption of Al and/or enhances Al excretion. Some epidemiological investigations suggested an association between chronic exposure to Al and risk of AD, although this relationship falls short of all the criteria generally attributed to causation. Future studies need to be more rigorous to truly test the validity of previous findings and in doing so attempt to identify dose-response relationships between Al and AD risk which may provide new routes to disease-modifying treatment of AD or possibly some lifestyle modification, to supplement existing symptomatic approaches.

  17. Aluminum and other metals in Alzheimer's disease: a review of potential therapy with chelating agents.

    Science.gov (United States)

    Domingo, Jose L

    2006-11-01

    Alzheimer's disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. Although the causes of AD remain still unknown, it seems that certain environmental factors may be involved in the etiology and pathogenesis of the disease. While AD is associated with the abnormal aggregation of beta-amyloid protein in the brain, evidence shows that certain metals play a role in the precipitation and cytotoxicity of this protein. Among these metals, the potential role of aluminum as a possible ethiopathogenic factor in AD has been especially controversial. This review is mainly focused on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of desferrioxamine and other Al chelating agents have been reviewed. The role of the metal chelator clioquinol in AD, which has been reported to reduce beta-amyloid plaques, presumably by chelation associated with copper and zinc, is also revised. Finally, the potential role of silicon in AD is also discussed.

  18. Aluminum in hippocampal neurons from humans with Alzheimer's disease.

    Science.gov (United States)

    Walton, J R

    2006-05-01

    Using a staining technique developed in 2004, we examined hippocampal tissue from autopsy-confirmed cases of Alzheimer's disease (AD) and controls. The stain disclosed aluminum in cells and subcellular structure. All pyramidal neurons in these aged specimens appeared to exhibit at least some degree of aluminum staining. Many displayed visible aluminum only in their nucleolus. At the other extreme were neurons that stained for aluminum throughout their nucleus and cytoplasm. The remainder exhibited intermediate degrees of staining. On the basis of their aluminum staining patterns, all pyramidal neurons could be classified into stages that indicated two distinct neuropathological processes, either (1) progressive increase of nuclear aluminum (often accompanied by granulovacuolar degeneration with granules that stain for aluminum) or (2) formation of neurofibrillary tangles (NFTs) in regions of aluminum-rich cytoplasm, especially in AD brain tissue. In the latter process, intraneuronal NFTs appeared to displace nuclei and then enucleate the affected neurons during the course of their transformation into extracellular NFTs. Given that the NFTs we observed in human neurons always developed in conjunction with cytoplasmic aluminum, we hypothesize that aluminum plays an important role in their formation and should therefore be reconsidered as a causative factor for AD.

  19. Microarray analysis on human neuroblastoma cells exposed to aluminum, β(1-42-amyloid or the β(1-42-amyloid aluminum complex.

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    Valentina Gatta

    Full Text Available BACKGROUND: A typical pathological feature of Alzheimer's disease (AD is the appearance in the brain of senile plaques made up of β-amyloid (Aβ and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al, plays a relevant role in affecting Aβ aggregation and neurotoxicity. METHODOLOGY: In this study, employing a microarray analysis of 35,129 genes, we investigated the effects induced by the exposure to the Aβ(1-42-Al (Aβ-Al complex on the gene expression profile of the neuronal-like cell line, SH-SY5Y. PRINCIPAL FINDINGS: The microarray assay indicated that, compared to Aβ or Al alone, exposure to Aβ-Al complex produced selective changes in gene expression. Some of the genes selectively over or underexpressed are directly related to AD. A further evaluation performed with Ingenuity Pathway analysis revealed that these genes are nodes of networks and pathways that are involved in the modulation of Ca(2+ homeostasis as well as in the regulation of glutamatergic transmission and synaptic plasticity. CONCLUSIONS AND SIGNIFICANCE: Aβ-Al appears to be largely involved in the molecular machinery that regulates neuronal as well as synaptic dysfunction and loss. Aβ-Al seems critical in modulating key AD-related pathways such as glutamatergic transmission, Ca(2+ homeostasis, oxidative stress, inflammation, and neuronal apoptosis.

  20. Immunotherapy for Alzheimer’s Disease: Past, Present and Future

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    Brian eSpencer

    2014-06-01

    Full Text Available Alzheimer’s disease (AD is an incurable, progressive, neurodegenerative disorder affecting over 5 million people in the US alone. This neurological disorder is characterized by widespread neurodegeneration throughout the association cortex and limbic system caused by deposition of Aβ resulting in the formation of plaques and tau resulting in the formation of neurofibrillary tangles. Active immunization for Aß showed promise in animal models of Alzheimer’s disease; however, the models were unable to predict the off-target immune effects in human patients. A few patients in the initial trial suffered cerebral meningoencephalitis. Recently, passive immunization has shown promise in the lab with less chance of off-target immune effects. Several trials have attempted using passive immunization for Aß, but again, positive end points have been elusive. The next generation of immunotherapy for Alzheimer’s disease may involve the marriage of anti-Aß antibodies with technology aimed at improving transport across the blood-brain barrier. Receptor mediated transport of antibodies may increase CNS exposure and improve the therapeutic index in the clinic.

  1. Doubly Phosphorylated Peptide Vaccines to Protect Transgenic P301S Mice against Alzheimer’s Disease Like Tau Aggregation

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    Monique Richter

    2014-07-01

    Full Text Available Intracellular neurofibrillary tangles and extracellular senile plaques are potential targets for active and passive immunotherapies. In this study we used the transgenic mouse model P301S for active immunizations with peptide vaccines composed of a double phosphorylated tau neoepitope (pSer202/pThr205, pThr212/pSer214, pThr231/pSer235 and an immunomodulatory T cell epitope from the tetanus toxin or tuberculosis antigen Ag85B. Importantly, the designed vaccine combining Alzheimer’s disease (AD specific B cell epitopes with foreign (bacterial T cell epitopes induced fast immune responses with high IgG1 titers after prophylactic immunization that subsequently decreased over the observation period. The effectiveness of the immunization was surveyed by evaluating the animal behavior, as well as the pathology in the brain by biochemical and histochemical techniques. Immunized mice clearly lived longer with reduced paralysis than placebo-treated mice. Additionally, they performed significantly better in rotarod and beam walk tests at the age of 20 weeks, indicating that the disease development was slowed down. Forty-eight weeks old vaccinated mice passed the beam walk test significantly better than control animals, which together with the increased survival rates undoubtedly prove the treatment effect. In conclusion, the data provide strong evidence that active immune therapies can reduce toxic effects of deposits formed in AD.

  2. Archview Lodge, Drumany, Letterkenny, Donegal.

    LENUS (Irish Health Repository)

    Colgan, N

    2015-10-23

    Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer\\'s disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer\\'s disease.

  3. Reduced miR-512 and the Elevated Expression of Its Targets cFLIP and MCL1 Localize to Neurons With Hyperphosphorylated Tau Protein in Alzheimer Disease.

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    Mezache, Louisa; Mikhail, Madison; Garofalo, Michela; Nuovo, Gerard J

    2015-10-01

    The cause for the neurofibrillary tangles and plaques in Alzheimer disease likely relates to an abnormal accumulation of their key components, which include β-amyloid and hyperphosphorylated tau protein. We segregated Alzheimer brain sections from people with end-stage disease into those with abundant hyperphosphorylated tau protein and those without and compared each to normal brains for global microRNA patterns. A significant reduced expression of several microRNAs, including miR-512, was evident in the Alzheimer brain sections with abundant hyperphosphorylated tau. Immunohistochemistry documented that 2 known targets of microRNA-512, cFLIP and MCL1, were significantly over expressed and each colocalized to neurons with the abnormal tau protein. Analysis for apoptosis including activated caspase-3, increased caspase-4 and caspase-8, apoptosis initiating factor, APAF-1 activity, and the TUNEL assay was negative in the areas where neurons showed hyperphosphorylated tau. MCM2 expression, a marker of neuroprogenitor cells, was significantly reduced in the Alzheimer sections that contained the hyperphosphorylated tau. These results suggest that a basic defect in Alzheimer disease may be the reduced microRNA-driven increased expression of proteins that may alter the apoptotic/antiapoptotic balance of neurons. This, in turn, could lead to the accumulation of key Alzheimer proteins such as hyperphosphorylated tau that ultimately prevent normal neuronal function and lead to disease symptomatology.

  4. Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1.

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    Itoh, Kyoko; Mitani, Maki; Kawamoto, Kunihiko; Futamura, Naonobu; Funakawa, Itaru; Jinnai, Kenji; Fushiki, Shinji

    2010-12-29

    Myotonic dystrophy (DM1) is known to be an adult-onset muscular dystrophy caused by the expansion of CTG repeats within the 3' untranslated region of the dystrophin myotonin protein kinase (DMPK) gene. The clinical features of DM1 include CNS symptoms, such as cognitive impairment and personality changes, the pathogenesis of which remains to be elucidated. We hypothesized that the distribution of neuropathological changes might be correlated with the extent of the length of the CTG repeats in the DMPK genes in DM1 patients. We studied the neuropathological changes in the brains of subjects with DM1 and investigated the extent of somatic instability in terms of CTG repeat expansion in the different brain regions of the same individuals by Southern blot analysis. The neuropathological changes included état criblé in the cerebral deep white matter and neurofibrillary tangles immunoreactive for phosphorylated tau in the hippocampus and entorhinal cortex, both of which were compatible with the subcortical dementia in DM1 patients. However, the length of the CTG repeats did not correlate with the regional differences in the extent of neuropathological changes. Our data suggested that pathomechanisms of dementia in DM1 might be more multifactorial rather than a toxic gain-of-function due to mutant RNA.

  5. The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease.

    Science.gov (United States)

    Grimm, Marcus O W; Mett, Janine; Hartmann, Tobias

    2016-10-26

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.

  6. TGF-β1 Protection against Aβ1–42-Induced Neuroinflammation and Neurodegeneration in Rats

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    Wei-Xing Shen

    2014-12-01

    Full Text Available Transforming growth factor (TGF-β1, a cytokine that can be expressed in the brain, is a key regulator of the brain’s responses to injury and inflammation. Alzheimer’s disease (AD, the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-β (Aβ plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-β1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-β1 via the intracerebroventricle (ICV in AD model rats, by Aβ1–42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-β1. The TGF-β1 administration after the Aβ1–42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP expression, elevated protein phosphatase (PP2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aβ1–42 injection alone. These findings demonstrate that TGF-β1 provides protection against AD neurodegeneration and suggest that the TGF-β1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.

  7. Alterations in protein phosphorylation in the amygdala of the 5XFamilial Alzheimer's disease animal model

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    Eun-Jeong Yang

    2017-04-01

    Full Text Available Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy. However, which molecular changes are responsible for the altered emotional states observed in AD remains to be elucidated. Here, we observed that the fear response as assessed by evaluating fear memory via a cued fear conditioning test was impaired in 5XFamilial AD (5XFAD mice, an animal model of AD. Compared to wild-type mice, 5XFAD mice showed changes in the phosphorylation of twelve proteins in the amygdala. Thus, our study provides twelve potential protein targets in the amygdala that may be responsible for the impairment in fear memory in AD.

  8. Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort.

    Science.gov (United States)

    Dolan, Hillary; Crain, Barbara; Troncoso, Juan; Resnick, Susan M; Zonderman, Alan B; Obrien, Richard J

    2010-08-01

    Although it is now accepted that asymptomatic cerebral infarcts are an important cause of dementia in the elderly, the relationship between atherosclerosis per se and dementia is controversial. Specifically, it is unclear whether atherosclerosis can cause the neuritic plaques and neurofibrillary tangles that define Alzheimer neuropathology and whether atherosclerosis, a potentially reversible risk factor, can influence cognition independent of brain infarcts. We examined the relationship between systemic atherosclerosis, Alzheimer type pathology, and dementia in autopsies from 200 participants in the Baltimore Longitudinal Study of Aging, a prospective study of the effect of aging on cognition, 175 of whom had complete body autopsies. Using a quantitative analysis of atherosclerosis in the aorta, heart, and intracranial vessels, we found no relationship between the degree of atherosclerosis in any of these systems and the degree of Alzheimer type brain pathology. However, we found that the presence of intracranial but not coronary or aortic atherosclerosis significantly increased the odds of dementia, independent of cerebral infarction. Given the large number of individuals with intracranial atherosclerosis in this cohort (136/200), the population attributable risk of dementia related to intracranial atherosclerosis (independent of infarction) is substantial and potentially reversible. Atherosclerosis of the intracranial arteries is an independent and important risk factor for dementia, suggesting potentially reversible pathways unrelated to Alzheimer pathology and stroke through which vascular changes may influence dementia risk.

  9. Emerging concepts in Alzheimer's disease.

    Science.gov (United States)

    Vinters, Harry V

    2015-01-01

    Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) is the most common neuropathologic substrate of dementia. It is characterized by synapse loss (predominantly within neocortex) as well as deposition of certain distinctive lesions (the result of protein misfolding) throughout the brain. The latter include senile plaques, composed mainly of an amyloid (Aβ) core and a neuritic component; neurofibrillary tangles, composed predominantly of hyperphosphorylated tau; and cerebral amyloid angiopathy, a microangiopathy affecting both cerebral cortical capillaries and arterioles and resulting from Aβ deposition within their walls or (in the case of capillaries) immediately adjacent brain parenchyma. In this article, I discuss the hypothesized role these lesions play in causing cerebral dysfunction, as well as CSF and neuroimaging biomarkers (for dementia) that are especially relevant as immunotherapeutic approaches are being developed to remove Aβ from the brain parenchyma. In addition, I address the role of neuropathology in characterizing the sequelae of new AD/SDAT therapies and helping to validate CSF and neuroimaging biomarkers of disease. Comorbidity of AD/SDAT and various types of cerebrovascular disease is a major theme in dementia research, especially as cognitive impairment develops in the oldest old, who are especially vulnerable to ischemic and hemorrhagic brain lesions.

  10. Intracerebroventricular administration of okadaic acid induces hippocampal glucose uptake dysfunction and tau phosphorylation.

    Science.gov (United States)

    Broetto, Núbia; Hansen, Fernanda; Brolese, Giovana; Batassini, Cristiane; Lirio, Franciane; Galland, Fabiana; Dos Santos, João Paulo Almeida; Dutra, Márcio Ferreira; Gonçalves, Carlos-Alberto

    2016-06-01

    Intraneuronal aggregates of neurofibrillary tangles (NFTs), together with beta-amyloid plaques and astrogliosis, are histological markers of Alzheimer's disease (AD). The underlying mechanism of sporadic AD remains poorly understood, but abnormal hyperphosphorylation of tau protein is suggested to have a role in NFTs genesis, which leads to neuronal dysfunction and death. Okadaic acid (OKA), a strong inhibitor of protein phosphatase 2A, has been used to induce dementia similar to AD in rats. We herein investigated the effect of intracerebroventricular (ICV) infusion of OKA (100 and 200ng) on hippocampal tau phosphorylation at Ser396, which is considered an important fibrillogenic tau protein site, and on glucose uptake, which is reduced early in AD. ICV infusion of OKA (at 200ng) induced a spatial cognitive deficit, hippocampal astrogliosis (based on GFAP increment) and increase in tau phosphorylation at site 396 in this model. Moreover, we observed a decreased glucose uptake in the hippocampal slices of OKA-treated rats. In vitro exposure of hippocampal slices to OKA altered tau phosphorylation at site 396, without any associated change in glucose uptake activity. Taken together, these findings further our understanding of OKA neurotoxicity, in vivo and vitro, particularly with regard to the role of tau phosphorylation, and reinforce the importance of the OKA dementia model for studying the neurochemical alterations that may occur in AD, such as NFTs and glucose hypometabolism. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer's disease

    Science.gov (United States)

    Jiao, S-S; Shen, L-L; Zhu, C; Bu, X-L; Liu, Y-H; Liu, C-H; Yao, X-Q; Zhang, L-L; Zhou, H-D; Walker, D G; Tan, J; Götz, J; Zhou, X-F; Wang, Y-J

    2016-01-01

    Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy. PMID:27701410

  12. Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

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    Sung-Soo Jang

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β (Aβ peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβ oligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβ levels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

  13. Does a positive Pittsburgh Compound B scan in a patient with dementia equal Alzheimer disease?

    Science.gov (United States)

    Ducharme, Simon; Guiot, Marie-Christine; Nikelski, James; Chertkow, Howard

    2013-07-01

    The clinical role of amyloid brain positron emission tomographic imaging in the diagnosis of Alzheimer disease is currently being formulated. The specificity of a positive amyloid scan is a matter of contention. An 83-year-old Canadian man presented with a 5-year history of predominantly short-term memory loss and functional impairment. Clinical evaluation revealed significant, gradually progressive short-term memory loss in the absence of any history of strokes or other neuropsychiatric symptoms. The patient met clinical criteria for probable Alzheimer disease but had a higher than expected burden of white matter disease on magnetic resonance imaging. A positron emission tomographic Pittsburgh Compound B scan was highly positive in typical Alzheimer disease distribution. The patient died of an intracerebral hemorrhage 6 months after the assessment. Autopsy revealed cerebral amyloid angiopathy in the complete absence of amyloid plaques or neurofibrillary tangles. This patient demonstrates that a positive Pittsburgh Compound B scan in a patient with clinical dementia meeting criteria for probable Alzheimer disease is not proof of an Alzheimer disease pathophysiological process. A positive Pittsburgh Compound B scan in typical Alzheimer disease distribution in a patient with dementia can be secondary to cerebral amyloid angiopathy alone.

  14. Pharmacotherapy Of Alzheimer′s Disease

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    Migalni Jasdeep

    2001-01-01

    Full Text Available Alzheimer′s disease is characterized by degeneration of various structures in the brain, with development of amyloid plaques and neurofibrillary tangles. Deficiencies of acetylcholine and other neurotransmitters also occur. Pharmacological treatment of the disease generally seeks to correct the histopathology, the biochemical derangements or their defects. The incidence of the disease is increasing worldwide. About 35% of people develop Alzheimer’s disease by age 75, and the percentage rises with age. By age 85, almost half of all people get the ailment. Reliable estimates of prevalence of Alzheimer′s disease in Indian subcontinent are not available as yet, however anecdotal data suggest a pattern consistent with worldwide trends. Physicians should be able to competently diagnose evaluate and initiate treatment in most patients with Alzheimer′s dementia. Hence, it is imperative that neurologists familiarize themselves with the pharmacological treatments of this challenging illness. The authors attempt to given an overview of the various current pharmacologic treatments available for the disease. Contemporary treatment of the memory disturbance in Alzheimer′s disease is to boost declining cholinergic function, which is characteristic of this disease. Therefore, the mainstay of current treatment is to use acetylcholinesterase inhibitors. The authors discuss the available acetylcholinesterase inhibitors and how they can be distinguished from each other on the basis of secondary pharmacologic properties. The article also discusses use of some other non-conventional and investigational drugs used for the treatment of Alzheimer′s disease.

  15. Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases.

    Science.gov (United States)

    Youssef, S A; Capucchio, M T; Rofina, J E; Chambers, J K; Uchida, K; Nakayama, H; Head, E

    2016-03-01

    According to the WHO, the proportion of people over 60 years is increasing and expected to reach 22% of total world's population in 2050. In parallel, recent animal demographic studies have shown that the life expectancy of pet dogs and cats is increasing. Brain aging is associated not only with molecular and morphological changes but also leads to different degrees of behavioral and cognitive dysfunction. Common age-related brain lesions in humans include brain atrophy, neuronal loss, amyloid plaques, cerebrovascular amyloid angiopathy, vascular mineralization, neurofibrillary tangles, meningeal osseous metaplasia, and accumulation of lipofuscin. In aging humans, the most common neurodegenerative disorder is Alzheimer's disease (AD), which progressively impairs cognition, behavior, and quality of life. Pathologic changes comparable to the lesions of AD are described in several other animal species, although their clinical significance and effect on cognitive function are poorly documented. This review describes the commonly reported age-associated neurologic lesions in domestic and laboratory animals and the relationship of these lesions to cognitive dysfunction. Also described are the comparative interspecies similarities and differences to AD and other human neurodegenerative diseases including Parkinson's disease and progressive supranuclear palsy, and the spontaneous and transgenic animal models of these diseases. © The Author(s) 2016.

  16. Brain pathologies in extreme old age.

    Science.gov (United States)

    Neltner, Janna H; Abner, Erin L; Jicha, Gregory A; Schmitt, Frederick A; Patel, Ela; Poon, Leonard W; Marla, Gearing; Green, Robert C; Davey, Adam; Johnson, Mary Ann; Jazwinski, S Michal; Kim, Sangkyu; Davis, Daron; Woodard, John L; Kryscio, Richard J; Van Eldik, Linda J; Nelson, Peter T

    2016-01-01

    With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Oxidative Stress as an Important Factor in the Pathophysiology of alzheimer's Disease

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    Tanise Gemelli,

    2013-06-01

    Full Text Available Oxidative stress has been associated to play a crucial role in the pathogenesis of many diseases, including neurodegenerative diseases. Alzheimer's disease is an age-related neurodegenerative disorder, which is recognized as the most common form of dementia. In this article, the aim was to review the involvement of oxidative stress on Alzheimer's disease. Alzheimer's disease is histopathologically characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles, the presence of oligomers of amyloid-? peptide and loss of synapses. Moreover, the brain and the nervous system are more prone to oxidative stress and oxidative damage influences the neurodegenerative diseases. However, increased oxidative damage, mitochondrial dysfunction, accumulation of oxidized aggregated proteins, inflammation, and defects in proteins constitute complex intertwined pathologies that lead to neuronal cell death. Mitochondrial mutations on deoxyribonucleic acid and oxidative stress contribute to aging, affecting different cell signaling systems, as well as the connectivity and neuronal cell death may lead to the largest risk factor for neurodegenerative diseases such as Alzheimer's Disease.

  18. Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?

    Directory of Open Access Journals (Sweden)

    Castillo-Carranza DL

    2013-12-01

    Full Text Available Diana L Castillo-Carranza,1,2 Marcos J Guerrero-Muñoz,1,2 Rakez Kayed1–31Mitchell Center for Neurodegenerative Diseases, 2Departments of Neurology, Neuroscience, and Cell Biology, 3Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX, USAAbstract: Alzheimer's disease (AD is characterized by the presence of amyloid plaques composed mainly of amyloid-β (Aβ protein. Overproduction or slow clearance of Aβ initiates a cascade of pathologic events that may lead to formation of neurofibrillary tangles, neuronal cell death, and dementia. Although immunotherapy in animal models has been demonstrated to be successful at removing plaques or prefibrillar forms of Aβ, clinical trials have yielded disappointing results. The lack of substantial cognitive improvement obtained by targeting Aβ raises the question of whether or not this is the correct target. Another important pathologic process in the AD brain is tau aggregation, which seems to become independent once initiated. Recent studies targeting tau in AD mouse models have displayed evidence of cognitive improvement, providing a novel therapeutic approach for the treatment of AD. In this review, we describe new advances in immunotherapy targeting Aβ peptide and tau protein, as well as future directions.Keywords: immunotherapy, Alzheimer's disease, β-amyloid, tau

  19. Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

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    Jackson George R

    2011-06-01

    Full Text Available Abstract Background The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I, and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

  20. Resilience to Alzheimer's disease: the role of physical activity.

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    Pedrinolla, Anna; Schena, Federico; Venturelli, Massimo

    2017-01-11

    Although Alzheimer's disease (AD) is a neurodegenerative pathology characterized by accumulation of β-amyloid plaques and neurofibrillary tangles at cerebral level, recent studies highlighted that AD might be the result of many altered physiological processes occurring at whole-organism level. The ability to adapt to stressors by "bending" but not "breaking" can be considered as "resilience". Individuals incline to withstand such pathophysiological challenges, can be considered more resilient than those that do not. Noticeably, recent literature provide evidence of several exercise-induced positive effects in AD patients including improved brain plasticity, increased adrenal sensitivity, increased vascular health, ameliorations of nitric oxide bioavailability and mitochondrial function. This review explores what resilience means in the AD milieu and the physiological mechanisms by which physical activity may mediate adaptive positive processes that enhance resilience. A comprehensive PubMed search was conducted to identify studies about the role of exercise in AD resiliency. The following terminology was applied: Alzheimer resilience, brain resilience, metabolic resilience, cardiovascular resilience, mitochondrial resilience and exercise resilience. Seventy-three studies were included. Five papers defined Alzheimer's resilience, 15 papers brain resilience, five cardiovascular resilience, one metabolic resilience, 11 mitochondrial resilience, and 7 exercise resilience. Other twenty-six paper were identified from reference list of authors' knowledge. knowing that disturbances in brain, neuroendocrine, vascular and mitochondria metabolism are important events in neurodegeneration and dementia development, the ability of exercise to trigger adaptive mechanisms might represent an important non-pharmacological strategy to improve resilience to AD.

  1. Aberrant proteolytic processing and therapeutic strategies in Alzheimer disease.

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    Tomita, Taisuke

    2017-05-01

    Amyloid-β peptide (Aβ) and tau are major components of senile plaques and neurofibrillary tangles, respectively, deposited in the brains of Alzheimer disease (AD) patients. Aβ is derived from amyloid-β precursor protein that is sequentially cleaved by two aspartate proteases, β- and γ-secretases. Secreted Aβ is then catabolized by several proteases. Several lines of evidence suggest that accumulation of Aβ by increased production or decreased degradation induces the tau-mediated neuronal toxicity and symptomatic manifestations of AD. Thus, the dynamics of cerebral Aβ, called as "Aβ economy", would be the mechanistic basis of AD pathogenesis. Partial loss of γ-secretase activity leads to the increased generation of toxic Aβ isoforms, indicating that activation of γ-secretase would provide a beneficial effect for AD. After extensive discovery and development efforts, BACE1, which is a β-secretase enzyme, has emerged as a prime drug target for lowering brain Aβ levels. Recent studies revealed the decreased clearance of Aβ in sporadic AD patients, suggesting the importance of the catabolic mechanism in the pathogenesis of AD. I will discuss with these proteolytic mechanisms involved in the regulation of Aβ economy, and development of effective treatment and diagnostics for AD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Discovery of the first dual GSK3β inhibitor/Nrf2 inducer. A new multitarget therapeutic strategy for Alzheimer’s disease

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    Gameiro, Isabel; Michalska, Patrycja; Tenti, Giammarco; Cores, Ángel; Buendia, Izaskun; Rojo, Ana I.; Georgakopoulos, Nikolaos D.; Hernández-Guijo, Jesús M.; Teresa Ramos, María; Wells, Geoffrey; López, Manuela G.; Cuadrado, Antonio; Menéndez, J. Carlos; León, Rafael

    2017-03-01

    The formation of neurofibrillary tangles (NFTs), oxidative stress and neuroinflammation have emerged as key targets for the treatment of Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder. These pathological hallmarks are closely related to the over-activity of the enzyme GSK3β and the downregulation of the defense pathway Nrf2-EpRE observed in AD patients. Herein, we report the synthesis and pharmacological evaluation of a new family of multitarget 2,4-dihydropyrano[2,3-c]pyrazoles as dual GSK3β inhibitors and Nrf2 inducers. These compounds are able to inhibit GSK3β and induce the Nrf2 phase II antioxidant and anti-inflammatory pathway at micromolar concentrations, showing interesting structure-activity relationships. The association of both activities has resulted in a remarkable anti-inflammatory ability with an interesting neuroprotective profile on in vitro models of neuronal death induced by oxidative stress and energy depletion and AD. Furthermore, none of the compounds exhibited in vitro neurotoxicity or hepatotoxicity and hence they had improved safety profiles compared to the known electrophilic Nrf2 inducers. In conclusion, the combination of both activities in this family of multitarget compounds confers them a notable interest for the development of lead compounds for the treatment of AD.

  3. proBDNF Accelerates Brain Amyloid-β Deposition and Learning and Memory Impairment in APPswePS1dE9 Transgenic Mice.

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    Chen, Jia; Zhang, Tao; Jiao, Shusheng; Zhou, Xinfu; Zhong, Jinhua; Wang, Yanjiang; Liu, Juan; Deng, Juan; Wang, Shuiping; Xu, Zhiqiang

    2017-01-01

    Alzheimer's disease (AD) is pathologically known for the amyloid-β (Aβ) deposition, neurofibrillary tangles, and neuronal loss in the brain. The precursor of brain-derived neurotrophic factor (proBDNF) before proteolysis has opposing functions to its mature form in neuronal survival and neurite growth. However, the role of proBDNF in the pathogenesis of AD remains unclear. To investigate the effects of proBDNF on neurons in vitro, and on learning and memory impairment and brain Aβ production in a transgenic AD mouse model (APPswePS1dE9). We here examined the effects of proBDNF on the viability (MTT assay) and neurite growth (morphologic measurement) of the primary neurons in vitro. After the intracerebroventricular injection of adeno-associated virus-proBDNF (AAV-proBDNF), we then investigated the learning and memory impairment (Morris water maze) and Aβ deposition in the brains of the AD mice. The results showed that proBDNF could inhibit neuronal viability and neurite growth in vitro, enhance Aβ levels, and accelerate its deposition in the brain, which was consistent with the learning and memory impairment of AD mice, likely dependent on the membrane receptor of p75NTR. Our findings suggest that proBDNF may exert a crucially negative effect during AD pathogenesis andprogression.

  4. Alterations in protein phosphorylation in the amygdala of the 5XFamilial Alzheimer's disease animal model.

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    Yang, Eun-Jeong; Mahmood, Usman; Kim, Hyunju; Choi, Moonseok; Choi, Yunjung; Lee, Jean-Pyo; Chang, Moon-Jeong; Kim, Hye-Sun

    2017-04-01

    Alzheimer's disease is the most common disease underlying dementia in humans. Two major neuropathological hallmarks of AD are neuritic plaques primarily composed of amyloid beta peptide and neurofibrillary tangles primarily composed of hyperphosphorylated tau. In addition to impaired memory function, AD patients often display neuropsychiatric symptoms and abnormal emotional states such as confusion, delusion, manic/depressive episodes and altered fear status. Brains from AD patients show atrophy of the amygdala which is involved in fear expression and emotional processing as well as hippocampal atrophy. However, which molecular changes are responsible for the altered emotional states observed in AD remains to be elucidated. Here, we observed that the fear response as assessed by evaluating fear memory via a cued fear conditioning test was impaired in 5XFamilial AD (5XFAD) mice, an animal model of AD. Compared to wild-type mice, 5XFAD mice showed changes in the phosphorylation of twelve proteins in the amygdala. Thus, our study provides twelve potential protein targets in the amygdala that may be responsible for the impairment in fear memory in AD. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  5. A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology

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    Mar Matarin

    2015-02-01

    Full Text Available We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of “amyloid” transgenic mice (mutant human APP, PSEN1, or APP/PSEN1 and “TAU” transgenic mice (mutant human MAPT gene. Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.

  6. Biological markers of Alzheimer?s disease

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    Leonardo Cruz de Souza

    2014-03-01

    Full Text Available The challenges for establishing an early diagnosis of Alzheimer’s disease (AD have created a need for biomarkers that reflect the core pathology of the disease. The cerebrospinal fluid (CSF levels of total Tau (T-tau, phosphorylated Tau (P-Tau and beta-amyloid peptide (Aβ42 reflect, respectively, neurofibrillary tangle and amyloid pathologies and are considered as surrogate markers of AD pathophysiology. The combination of low Aβ42 and high levels of T-tau and P-Tau can accurately identify patients with AD at early stages, even before the development of dementia. The combined analysis of the CSF biomarkers is also helpful for the differential diagnosis between AD and other degenerative dementias. The development of these CSF biomarkers has evolved to a novel diagnostic definition of the disease. The identification of a specific clinical phenotype combined with the in vivo evidence of pathophysiological markers offers the possibility to make a diagnosis of AD before the dementia stage with high specificity.

  7. Increased insulin-like growth factor-1 levels in cerebrospinal fluid of advanced subacute sclerosing panencephalitis patients.

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    Yılmaz, Deniz; Yüksel, Deniz; Gökkurt, Didem; Oguz, Hava; Anlar, Banu

    2016-07-01

    Subacute sclerosing panencephalitis (SSPE) is a progressive, lethal disease. Brain histopathology in certain SSPE patients shows, neurofibrillary tangles composed of abnormally phosphorylated, microtubule-associated protein tau (PHF-tau). Because the, phosphorylation of tau is inhibited by insulin and insulin-like growth factor-1 (IGF-1), we investigated cerebrospinal fluid (CSF) insulin and IGF-1 levels in SSPE patients. In this study CSF IGF-1 and insulin levels of 45 SSPE and 25 age-matched control patients were investigated. CSF IGF-1 levels were significantly higher in SSPE patients at stage 4, compared to other stages (p 0.05). CSF insulin and IGF-1 levels were both positively correlated with serum measles IgG. The correlation between CSF insulin and IGF-1 levels and serum measles virus IgG titer may be the result of, insulin activating IGF-1 receptors, and consequently, IGF-1 stimulating, plasma cells and enhancing IgG production. Increased IGF-1 may also, inhibit the phosphorylation of tau. Further studies examining the, correlation between IGF-1, insulin, tau, and PHF-tau levels in the same, patients may clarify any possible pathogenetic relation between these, pathways. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  8. Neuroprotective, Anti-Amyloidogenic and Neurotrophic Effects of Apigenin in an Alzheimer’s Disease Mouse Model

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    Lu Zhang

    2013-08-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles in the brain. Amyloid-β peptides (Aβ are considered to play a critical role in the onset and progression of AD. Apigenin (4',5,7-trihydroxyflavone is a pharmacologically active agent. Even though some evidence suggests that it has potential neuroprotective effects, no preexisting study has reported any therapeutic effects of apigenin in AD models. In the present study, we examined the effects of apigenin on cognitive function in APP/PS1 double transgenic AD mice and explored its mechanism(s of action. Three-month oral treatment with apigenin rescued learning deficits and relieved memory retention in APP/PS1 mice. Apigenin also showed effects affecting APP processing and preventing Aβ burden due to the down-regulation of BACE1 and β-CTF levels, the relief of Aβ deposition, and the decrease of insoluble Aβ levels. Moreover, apigenin exhibited superoxide anion scavenging effects and improved antioxidative enzyme activity of superoxide dismutase and glutathione peroxidase. In addition, apigenin restored neurotrophic ERK/CREB/BDNF pathway in the cerebral cortex. In conclusion, apigenin may ameliorate AD-associated learning and memory impairment through relieving Aβ burden, suppressing amyloidogenic process, inhibiting oxidative stress, and restoring ERK/CREB/BDNF pathway. Therefore, apigenin appears to represent an alternative medication for the prevention and/or therapy of AD.

  9. Voxel-based Morphometry of Brain MRI in Normal Aging and Alzheimer's Disease.

    Science.gov (United States)

    Matsuda, Hiroshi

    2013-02-01

    Voxel-based morphometry (VBM) using structural brain MRI has been widely used for assessment of normal aging and Alzheimer's disease (AD). VBM of MRI data comprises segmentation into gray matter, white matter, and cerebrospinal fluid partitions, anatomical standardization of all the images to the same stereotactic space using linear affine transformation and further non-linear warping, smoothing, and finally performing a statistical analysis. Two techniques for VBM are commonly used, optimized VBM using statistical parametric mapping (SPM) 2 or SPM5 with non-linear warping based on discrete cosine transforms and SPM8 plus non-linear warping based on diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL). In normal aging, most cortical regions prominently in frontal and insular areas have been reported to show age-related gray matter atrophy. In contrast, specific structures such as amygdala, hippocampus, and thalamus have been reported to be preserved in normal aging. On the other hand, VBM studies have demonstrated progression of atrophy mapping upstream to Braak's stages of neurofibrillary tangle deposition in AD. The earliest atrophy takes place in medial temporal structures. Stand-alone VBM software using SPM8 plus DARTEL running on Windows has been newly developed as an adjunct to the clinical assessment of AD. This software provides a Z-score map as a consequence of comparison of a patient's MRI with a normal database.

  10. Original article. Protective effect of resveratrol against neuronal damage through oxidative stress in cerebral hemisphere of aluminum and fluoride treated rats

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    Nalagoni Chandra Shakar Reddy

    2016-06-01

    Full Text Available Aluminum has no defined biological function and it is potentially involved in the pathogenesis of neurodegenerative disorders. Furthermore, the presence of fluoride causes more aluminum to accumulate in the brain, resulting in increased neuronal damage. In recent years, resveratrol through its ameliorative effects was found to be a neuroprotectant. This study reports the protective effects of resveratrol on combined aluminum and fluoride induced neuronal damage through oxidative stress in rats. Protective effects of resveratrol (30 mg/kg b.w on markers of oxidative stress were determined in rats exposed to aluminum chloride (100 mg/kg b.w along with sodium fluoride (10 mg/kg b.w for 8 weeks. The results showed a statistically significant (p<0.05 increase in lipid peroxidation (LPx as well as a significant (p<0.05 decrease in superoxide dismutase and catalase activity. Enlarged cells, neurofibrillary tangles, and vacuolar spaces showing oxidative stress in the cerebral cortex were also observed in hematoxylin and eosin stained sections in aluminum and fluoride treated rats. Administration of resveratrol along with aluminum + fluoride showed significant reversal of oxidative stress and neuronal damage in rats. Thus resveratrol potentially acts as a neuroprotectant against aluminum chloride + sodium fluoride induced neuronal damage through its anti-oxidant efficacy.

  11. Behavioral Improvement after Chronic Administration of Coenzyme Q10 in P301S Transgenic Mice

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    Elipenahli, Ceyhan; Stack, Cliona; Jainuddin, Shari; Gerges, Meri; Yang, Lichuan; Starkov, Anatoly; Beal, M. Flint; Dumont, Magali

    2012-01-01

    Coenzyme Q10 is a key component of the electron transport chain which plays an essential role in ATP production and also has antioxidant effects. Neuroprotective effects of coenzyme Q10 have been reported in both in vitro and in vivo models of neurodegenerative diseases. However, its effects have not been studied in cells or in animals with tau induced pathology. In this report, we administered coenzyme Q10 to transgenic mice with the P301S tau mutation, which causes fronto-temporal dementia in man. These mice develop tau hyperphosphorylation and neurofibrillary tangles in the brain. Coenzyme Q10 improved survival and behavioral deficits in the P301S mice. There was a modest reduction in phosphorylated tau in the cortex of P301S mice. We also examined the effects of coenzyme Q10 treatment on the electron transport chain enzymes, the mitochondrial antioxidant enzymes, and the tricarboxylic acid cycle. There was a significant increase in complex I activity and protein levels, and a reduction in lipid peroxidation. Our data show that coenzyme Q10 significantly improved behavioral deficits and survival in transgenic mice with the P301S tau mutation, upregulated key enzymes of the electron transport chain, and reduced oxidative stress. PMID:21971408

  12. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

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    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Neurodegenerative 'overlap' syndrome: Clinical and pathological features of Parkinson's disease, motor neuron disease, and Alzheimer's disease.

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    Uitti, R J; Berry, K; Yasuhara, O; Eisen, A; Feldman, H; McGeer, P L; Calne, D B

    1995-07-01

    Parkinson's disease (PD), Alzheimer's disease (AD), and motor neuron disease (MND) share epidemiological, clinical, and pathological features. Few studies have reported comprehensively on individuals who demonstrate a neurodegenerative 'overlap' syndrome, comprising idiopathic parkinsonism, dementia, and motor neuron dysfunction. We describe clinical, electrophysiological, and pathological features in six patients with neurodegenerative 'overlap' syndrome. All had cardinal features of PD (duration 6-26 years), and any mixture of dementia (slowly advancing), fasciculations, hyperreflexia, Babinski signs and mild atrophy and weakness of distal muscles (slowly progressive). EMG often demonstrated a lack of denervation in conjunction with abnormal MEPs (high thresholds). Patients had either 6FD-PET or pathological studies consistent with PD. Pathological studies also demonstrated moderate numbers of neurofibrillary tangles and plaque formation, typically with sparing of motor neurons in the spinal cord. We conclude that neurodegenerative 'overlap' syndrome may represent forme frustes of traditionally accepted diagnostic categories. Patients with parkinsonism, fasciculations, hyperreflexia and mild atrophy are unlikely to demonstrate active denervation on EMG; their prognosis is better than for classical MND. Neurodegenerative overlap syndrome (clinicopathological mixtures of PD, AD, and MND) may develop in some individuals as a reflection of common etiology, pathogenesis or susceptibility.

  14. Systemic inflammation, blood-brain barrier vulnerability and cognitive / non-cognitive symptoms in Alzheimer disease: Relevance to pathogenesis and therapy

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    Shuko eTakeda

    2014-07-01

    Full Text Available The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plaques and neurofibrillary tangles, accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non-cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood-brain barrier dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive / non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions.

  15. The Involvement of Post-Translational Modifications in Alzheimer's Disease.

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    Marcelli, S; Corbo, Massimo; Iannuzzi, Filomena; Negri, Lucia; Blandini, Fabio; Nisticò, Robert; Feligioni, M

    2017-05-04

    Alzheimer’s disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Ginsenoside Rd attenuates beta-amyloid-induced tau phosphorylation by altering the functional balance of glycogen synthase kinase 3beta and protein phosphatase 2A.

    Science.gov (United States)

    Li, Ling; Liu, Zhirong; Liu, Juanfang; Tai, Xuhui; Hu, Xinghua; Liu, Xuedong; Wu, Zhongliang; Zhang, Guangyun; Shi, Ming; Zhao, Gang

    2013-06-01

    Neurofibrillary tangles are aggregates of hyperphosphorylated tau that are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by a balance of kinase and phosphatase activities. Our previous study has demonstrated that ginsenoside Rd, one of the principal active ingredients of Pana notoginseng, inhibits okadaic acid-induced tau phosphorylation in vivo and in vitro, but the underlying mechanism(s) is unknown. In this study, we showed that ginsenoside Rd pretreatment inhibited tau phosphorylation at multiple sites in beta-amyloid (Aβ)-treated cultured cortical neurons, and in vivo in both a rat and transgenic mouse model. Ginsenoside Rd not only reduced Aβ-induced increased expression of glycogen synthase kinase 3beta (GSK-3β), the most important kinase involved in tau phosphorylation, but also inhibited its activity by enhancing and attenuating its phosphorylation at Ser9 and Tyr216, respectively. Moreover, ginsenoside Rd enhanced the activity of protein phosphatase 2A (PP-2A), a key phosphatase involved in tau dephosphorylation. Finally, an in vitro biochemical assay revealed that ginsenoside Rd directly affected GSK-3β and PP-2A activities. Thus, our findings provide the first evidence that ginsenoside Rd attenuates Aβ-induced pathological tau phosphorylation by altering the functional balance of GSK-3β and PP-2A. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Promoting brain health through exercise and diet in older adults: a physiological perspective.

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    Jackson, Philippa A; Pialoux, Vincent; Corbett, Dale; Drogos, Lauren; Erickson, Kirk I; Eskes, Gail A; Poulin, Marc J

    2016-08-15

    The rise in incidence of age-related cognitive impairment is a global health concern. Ageing is associated with a number of changes in the brain that, collectively, contribute to the declines in cognitive function observed in older adults. Structurally, the ageing brain atrophies as white and grey matter volumes decrease. Oxidative stress and inflammation promote endothelial dysfunction thereby hampering cerebral perfusion and thus delivery of energy substrates and nutrients. Further, the development of amyloid plaques and neurofibrillary tangles contributes to neuronal loss. Of interest, there are substantial inter-individual differences in the degree to which these physical and functional changes impact upon cognitive function as we grow older. This review describes how engaging in physical activity and cognitive activities and adhering to a Mediterranean style diet promote 'brain health'. From a physiological perspective, we discuss the effects of these modifiable lifestyle behaviours on the brain, and how some recent human trials are beginning to show some promise as to the effectiveness of lifestyle behaviours in combating cognitive impairment. Moreover, we propose that these lifestyle behaviours, through numerous mechanisms, serve to increase brain, cerebrovascular and cognitive reserve, thereby preserving and enhancing cognitive function for longer. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  18. Role of miR-211 in Neuronal Differentiation and Viability: Implications to Pathogenesis of Alzheimer’s Disease

    Science.gov (United States)

    Fan, Chunying; Wu, Qi; Ye, Xiaoyang; Luo, Hongxue; Yan, Dongdong; Xiong, Yi; Zhu, Haili; Diao, Yarui; Zhang, Wei; Wan, Jun

    2016-01-01

    Alzheimer’s disease (AD) is an age-related irreversible neurodegenerative disorder characterized by extracellular β Amyloid(Aβ) deposition, intracellular neurofibrillary tangles and neuronal loss. The dysfunction of neurogenesis and increased degeneration of neurons contribute to the pathogenesis of AD. We now report that miR-211-5p, a small non-coding RNA, can impair neurite differentiation by directly targeting NUAK1, decrease neuronal viability and accelerate the progression of Aβ-induced pathologies. In this study, we observed that during embryonic development, the expression levels of miR-211-5p were down-regulated in the normal cerebral cortexes of mice. However, in APPswe/PS1ΔE9 double transgenic adult mice, it was up-regulated from 9 months of age compared to that of the age-matched wild type mice. Studies in primary cortical neuron cultures demonstrated that miR-211-5p can inhibit neurite growth and branching via NUAK1 repression and decrease mature neuron viability. The impairments were more obvious under the action of Aβ. Our data showed that miR-211-5p could inhibit cortical neuron differentiation and survival, which may contribute to the synaptic failure, neuronal loss and cognitive dysfunction in AD. PMID:27458373

  19. Research progress in animal models and stem cell therapy for Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Han F

    2014-12-01

    Full Text Available Fabin Han,1,2 Wei Wang1, Chao Chen1 1Centre for Stem Cells and Regenerative Medicine, 2Department of Neurology, Liaocheng People’s Hospital/The Affiliated Liaocheng Hospital, Taishan Medical University, Shandong, People’s Republic of China Abstract: Alzheimer’s disease (AD causes degeneration of brain neurons and leads to memory loss and cognitive impairment. Since current therapeutic strategies cannot cure the disease, stem cell therapy represents a powerful tool for the treatment of AD. We first review the advances in molecular pathogenesis and animal models of AD and then discuss recent clinical studies using small molecules and immunoglobulins to target amyloid-beta plaques for AD therapy. Finally, we discuss stem cell therapy for AD using neural stem cells, olfactory ensheathing cells, embryonic stem cells, and mesenchymal stem cell from bone marrow, umbilical cord, and umbilical cord blood. In particular, patient-specific induced pluripotent stem cells are proposed as a future treatment for AD. Keywords: amyloid-beta plaque, neurofibrillary tangle, neural stem cell, olfactory ensheathing cell, mesenchymal stem cell, induced pluripotent stem cell

  20. Hologram QSAR Models of a Series of 6-Arylquinazolin-4-Amine Inhibitors of a New Alzheimer’s Disease Target: Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase-1A Enzyme

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    Felipe Dias Leal

    2015-03-01

    Full Text Available Dual specificity tyrosine-phosphorylation-regulated kinase-1A (DYRK1A is an enzyme directly involved in Alzheimer’s disease, since its increased expression leads to β-amyloidosis, Tau protein aggregation, and subsequent formation of neurofibrillary tangles. Hologram quantitative structure-activity relationship (HQSAR, 2D fragment-based models were developed for a series of 6-arylquinazolin-4-amine inhibitors (36 training, 10 test of DYRK1A. The best HQSAR model (q2 = 0.757; SEcv = 0.493; R2 = 0.937; SE = 0.251; R2pred = 0.659 presents high goodness-of-fit (R2 > 0.9, as well as high internal (q2 > 0.7 and external (R2pred > 0.5 predictive power. The fragments that increase and decrease the biological activity values were addressed using the colored atomic contribution maps provided by the method. The HQSAR contribution map of the best model is an important tool to understand the activity profiles of new derivatives and may provide information for further design of novel DYRK1A inhibitors.

  1. The model Caenorhabditis elegans in diabetes mellitus and Alzheimer's disease.

    Science.gov (United States)

    Morcos, Michael; Hutter, Harald

    2009-01-01

    Diabetes mellitus, with its complications, and Alzheimer's disease (AD) share many similarities. Both are age-related and associated with enhanced formation of advanced glycation endproducts (AGEs) and oxidative stress, factors that can be observed during the normal aging process as well. AGE deposits can be found in areas of atherosclerotic lesions in diabetes and in senile plaques and neurofibrillary tangles in AD. A classical model organism in aging research is the nematode Caenorhabditis elegans (C. elegans). Though C. elegans lacks a vascular system, it has been introduced in diabetes and AD research since it shares many similarities at the molecular level to pathological processes found in humans. AGEs accumulate in C. elegans, and increased AGE-formation and mitochondrial AGE-modification are responsible for increased oxidative stress and limiting life span. Moreover, C. elegans has an accessible and well characterized nervous system and features several genes homologous to human genes implicated in AD like amyloid-beta protein precursor, presenilins and tau. In addition, human genes linked to AD, such as amyloid-beta or tau, can be expressed and studied in C. elegans. So far, C. elegans research has contributed to a better understanding of the function of AD-related genes and the development of this disease.

  2. Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain.

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    Butterfield, D Allan; Di Domenico, Fabio; Barone, Eugenio

    2014-09-01

    Alzheimer disease (AD) is the most common form of dementia among the elderly and is characterized by progressive loss of memory and cognition. Epidemiological data show that the incidence of AD increases with age and doubles every 5 years after 65 years of age. From a neuropathological point of view, amyloid-β-peptide (Aβ) leads to senile plaques, which, together with hyperphosphorylated tau-based neurofibrillary tangles and synapse loss, are the principal pathological hallmarks of AD. Aβ is associated with the formation of reactive oxygen (ROS) and nitrogen (RNS) species, and induces calcium-dependent excitotoxicity, impairment of cellular respiration, and alteration of synaptic functions associated with learning and memory. Oxidative stress was found to be associated with type 2 diabetes mellitus (T2DM), which (i) represents another prevalent disease associated with obesity and often aging, and (ii) is considered to be a risk factor for AD development. T2DM is characterized by high blood glucose levels resulting from increased hepatic glucose production, impaired insulin production and peripheral insulin resistance, which close resemble to the brain insulin resistance observed in AD patients. Furthermore, growing evidence suggests that oxidative stress plays a pivotal role in the development of insulin resistance and vice versa. This review article provides molecular aspects and the pharmacological approaches from both preclinical and clinical data interpreted from the point of view of oxidative stress with the aim of highlighting progresses in this field. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. N-Alkyl Carbazole Derivatives as New Tools for Alzheimer’s Disease: Preliminary Studies

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    Carmela Saturnino

    2014-07-01

    Full Text Available Alzheimer’s disease (AD is a progressive and age-related neurodegenerative disorder affecting brain cells and is the most common form of “dementia”, because of the cognitive detriment which takes place. Neuronal disruption represents its major feature, due to the cytosolic accumulation of amyloid β-peptide (Aβ which leads to senile plaques formation and intracellular neurofibrillary tangles. Many studies have focused on the design and therapeutic use of new molecules able to inhibit Aβ aggregation. In this context, we evaluated the ability of two recently synthesized series of N-alkyl carbazole derivatives to increase the Aβ soluble forms, through molecular docking simulations and in vitro experiments. Our data evidenced that two carbazole derivatives, the most active, adopt distinct binding modes involving key residues for Aβ fibrillization. They exhibit a good interfering activity on Aβ aggregation in mouse (N2a cells, stably expressing wild-type human amyloid precursor protein (APP 695. These preliminary results are promising and we are confident that the N-alkyl carbazole derivatives may encourage next future studies needed for enlarging the knowledge about the AD disease approach.

  4. A review study on medicinal plants used in the treatment of learning and memory impairments

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    Nahid Jivad

    2014-10-01

    Full Text Available Alzheimer's disease (AD is a progressive brain disorder that gradually impairs the person's memory and ability to learn, reasoning, judgment, communication and daily activities. AD is characterized clinically by cognitive impairment and pathologically by the deposition of β amyloid plaques and neurofibrillary tangles, and the degeneration of the cholinergic basal forebrain. During the progression of AD patients may produce changes in personality and behavior, such as anxiety, paranoia, confusion, hallucinations and also to experience delusions and fantasies. The first neurotransmitter defect discovered in AD involved acetylcholine as cholinergic function is required for short-term memory. Oxidative stress may underlie the progressive neurodegeneration characteristic of AD. Brain structures supporting memory are uniquely sensitive to oxidative stress due to their elevated demand for oxygen. The neurodegenerative process in AD may involve β amyloid toxicity. Neurotoxicity of β amyloid appears to involve oxidative stress. Currently, there is no cure for this disease but in new treatments, reveals a new horizon on the biology of this disease. This paper reviews the effects of a number of commonly used types of herbal medicines for the treatment of AD. The objective of this article was to review evidences from controlled studies in order to determine whether herbs can be useful in the treatment of cognitive disorders in the elderly.

  5. p62 improves AD-like pathology by increasing autophagy.

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    Caccamo, A; Ferreira, E; Branca, C; Oddo, S

    2017-06-01

    The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis and Alzheimer's disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β (Aβ) aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in Aβ levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aβ were due to an increase in autophagy. To this end, we showed that removing the LC3-interacting region of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aβ. Overall, we believe these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover.

  6. p62 improves AD-like pathology by increasing autophagy

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    Caccamo, Antonella; Ferreira, Eric; Branca, Caterina; Oddo, Salvatore

    2016-01-01

    The multifunctional protein p62 is associated with neuropathological inclusions in several neurodegenerative disorders, including frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Alzheimer’s disease (AD). Strong evidence shows that in AD, p62 immunoreactivity is associated with neurofibrillary tangles and is involved in tau degradation. However, it remains to be determined whether p62 also plays a role in regulating amyloid-β aggregation and degradation. Using a gene therapy approach, here we show that increasing brain p62 expression rescues cognitive deficits in APP/PS1 mice, a widely used animal model of AD. The cognitive improvement was associated with a decrease in amyloid-β levels and plaque load. Using complementary genetic and pharmacologic approaches, we found that the p62-mediated changes in Aβ were due to an increase in autophagy. To this end, we showed that removing the LIR domain of p62, which facilitates p62-mediated selective autophagy, or blocking autophagy with a pharmacological inhibitor, was sufficient to prevent the decrease in Aβ. Overall, these data provide the first direct in vivo evidence showing that p62 regulates Aβ turnover. PMID:27573878

  7. Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction.

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    Pandey, Anjali; Bani, Sarang; Dutt, Prabhu; Kumar Satti, Naresh; Avtar Suri, Krishan; Nabi Qazi, Ghulam

    2017-11-03

    Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of β amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid β-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both β- and γ- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Aβ processing, protection against oxidative stress and anti-inflammatory effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Role of melatonin in Alzheimer-like neurodegeneration.

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    Wang, Jian-zhi; Wang, Ze-fen

    2006-01-01

    Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.

  9. Alzheimer's Disease: Another Target for Heparin Therapy

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    Luigi Bergamaschini

    2009-01-01

    Full Text Available Alzheimer's disease (AD is the leading cause of dementia and cognitive decline in the elderly. Brain tissue changes indicate that the two main proteins involved in AD are amyloid-β(A-β, which is associated with the formation of senile amyloid plaques, and tau, which is associated with the formation of neurofibrillary tangles. Although a central role for A-β in the pathogenesis of AD is indisputable, considerable evidence indicates that A-β production is not the sole culprit in AD pathology. AD is also accompanied by an inflammatory response that contributes to irreversible changes in neuronal viability and brain function, and accumulating evidence supports the pivotal role of complement and contact systems in its pathogenesis and progression. The complexity of AD pathology provides numerous potential targets for therapeutic interventions. Compounds that interact directly with A-β protein or interfere with its production and/or aggregation can reduce the inflammatory and neurotoxic effects of A-β, and heparin, a glycosaminoglycan mixture currently used in the prophylaxis and treatment of thrombosis, might be a candidate, as recent research has been extended to consider its nonanticoagulant properties, including its modulation of various proteases and anti-inflammatory activity.

  10. The Pathogenesis of Alzheimer's Disease: A Reevaluation of the “Amyloid Cascade Hypothesis”

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    R. A. Armstrong

    2011-01-01

    Full Text Available The most influential theory to explain the pathogenesis of Alzheimer's disease (AD has been the “Amyloid Cascade Hypothesis” (ACH first formulated in 1992. The ACH proposes that the deposition of β-amyloid (Aβ is the initial pathological event in AD leading to the formation of senile plaques (SPs and then to neurofibrillary tangles (NFTs death of neurons, and ultimately dementia. This paper examines two questions regarding the ACH: (1 is there a relationship between the pathogenesis of SPs and NFTs, and (2 what is the relationship of these lesions to disease pathogenesis? These questions are examined in relation to studies of the morphology and molecular determinants of SPs and NFTs, the effects of gene mutation, degeneration induced by head injury, the effects of experimentally induced brain lesions, transgenic studies, and the degeneration of anatomical pathways. It was concluded that SPs and NFTs develop independently and may be the products rather than the causes of neurodegeneration in AD. A modification to the ACH is proposed which may better explain the pathogenesis of AD, especially of late-onset cases of the disease.

  11. Simvastatin ameliorates cognitive impairments via inhibition of oxidative stress‑induced apoptosis of hippocampal cells through the ERK/AKT signaling pathway in a rat model of senile dementia.

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    Liu, Wenting; Zhao, Yan; Zhang, Xinyu; Ji, Jiangang

    2018-01-01

    Senile dementia is a degenerative disease of the nervous system associated with cognitive impairments, memory disorders, executive dysfunctions, cognitive decline and dementia. Previous reports suggested that simvastatin presents ameliorative effects in the progression of senile dementia. However, the mechanism underlying simvastatin‑mediated improvements of cognitive competence during the progression of senile dementia remains to be elucidated. In the present study, a potential mechanism underlying simvastatin activity in hippocampal cells, was investigated. Results of the present study demonstrated that simvastatin significantly improved cognitive impairments, memory competence, amyloid plaques, loss of neurons and synapses, neurofibrillary tangles and oxidative damage in experimental rats. Results of the present study demonstrated that administration of simvastatin regulates superoxide dismutase, reactive oxygen species, catalase and glutathione in oxidative stress processes in hippocampal cells. Apoptosis of hippocampal cells was suppressed by simvastatin treatment in rats with senile dementia. Notably, the administration of simvastatin inhibited activating transcription factor‑6‑mediated extracellular signal‑regulated kinase/AKT serine/threonine kinase (ERK/AKT) signaling pathway in hippocampal cells. Taken together, the preclinical results of the present study indicate that simvastatin is efficient in preventing memory lapse and inhibiting apoptosis of hippocampal cells via the ERK/AKT signaling pathway, which may in the future improve cognitive decline and dementia in patients.

  12. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

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    C. Cheignon

    2018-04-01

    Full Text Available Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD, an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS when bound to the amyloid-β (Aβ. The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …. This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level. Keywords: Oxidative stress, Amyloid beta peptide, Metal-ions, Reactive oxygen species, Oxidative damages

  13. Palmitoylethanolamide Dampens Reactive Astrogliosis and Improves Neuronal Trophic Support in a Triple Transgenic Model of Alzheimer’s Disease: In Vitro and In Vivo Evidence

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    Maria Rosanna Bronzuoli

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disorder responsible for the majority of dementia cases in elderly people. It is widely accepted that the main hallmarks of AD are not only senile plaques and neurofibrillary tangles but also reactive astrogliosis, which often precedes detrimental deposits and neuronal atrophy. Such phenomenon facilitates the regeneration of neural networks; however, under some circumstances, like in AD, reactive astrogliosis is detrimental, depriving neurons of the homeostatic support, thus contributing to neuronal loss. We investigated the presence of reactive astrogliosis in 3×Tg-AD mice and the effects of palmitoylethanolamide (PEA, a well-documented anti-inflammatory molecule, by in vitro and in vivo studies. In vitro results revealed a basal reactive state in primary cortical 3×Tg-AD-derived astrocytes and the ability of PEA to counteract such phenomenon and improve viability of 3×Tg-AD-derived neurons. In vivo observations, performed using ultramicronized- (um- PEA, a formulation endowed with best bioavailability, confirmed the efficacy of this compound. Moreover, the schedule of treatment, mimicking the clinic use (chronic daily administration, revealed its beneficial pharmacological properties in dampening reactive astrogliosis and promoting the glial neurosupportive function. Collectively, our results encourage further investigation on PEA effects, suggesting it as an alternative or adjunct treatment approach for innovative AD therapy.

  14. The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex.

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    Moritz M Hettich

    Full Text Available Alzheimer's disease (AD, the most common form of dementia in the elderly, is characterized by two neuropathological hallmarks: senile plaques, which are composed of Aβ peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated TAU protein. Diabetic patients with dysregulated insulin signalling are at increased risk of developing AD. Further, several animal models of diabetes show increased Aβ expression and hyperphosphorylated tau. As we have shown recently, the anti-diabetic drug metformin is capable of dephosphorylating tau at AD-relevant phospho-sites. Here, we investigated the effect of metformin on the main amyloidogenic enzyme BACE1 and, thus, on the production of Aβ peptides, the second pathological hallmark of AD. We find similar results in cultures of primary neurons, a human cell line model of AD and in vivo in mice. We show that treatment with metformin decreases BACE1 protein expression by interfering with an mRNA-protein complex that contains the ubiquitin ligase MID1, thereby reducing BACE1 activity. Together with our previous findings these results indicate that metformin may target both pathological hallmarks of AD and may be of therapeutic value for treating and/or preventing AD.

  15. Increased Cerebrospinal Fluid Production as a Possible Mechanism Underlying Caffeine's Protective Effect against Alzheimer's Disease

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    Peter Wostyn

    2011-01-01

    Full Text Available Alzheimer's disease (AD, the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF production, associated with the increased expression of Na+-K+ ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

  16. Frontotemporal dementia with parkinsonism linked to chromosome 17 with the MAPT R406W mutation presenting with a broad distribution of abundant senile plaques.

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    Ishida, Chiho; Kobayashi, Katsuji; Kitamura, Tatsuru; Ujike, Hiroshi; Iwasa, Kazuo; Yamada, Masahito

    2015-02-01

    We report the autopsy results of a patient with familial dementia who was diagnosed as having frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with an R406W mutation in the microtubule-associated protein tau (MAPT) gene. This patient showed Alzheimer's disease (AD)-like clinical manifestations from the age of 59, with reduced β-amyloid1-42 (Aβ42 ) and elevated total and phosphorylated tau levels in the cerebrospinal fluid. He did not present with any apparent parkinsonism throughout the disease course. His autopsy at age 73 showed atrophy and neurodegeneration in many brain regions, particularly in the antero-medial temporal cortex and hippocampus, followed by the frontal lobes, with abundant neurofibrillary tangles. In addition, a diffuse distribution of Aβ-positive senile plaques, including many neuritic plaques, was observed and classified as stage C according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. These results suggest that analyzing of the MAPT gene is essential for diagnosing familial dementia, even if amyloid markers such as Aβ42 in the cerebrospinal fluid and amyloid imaging are positive, or if neuropathological findings indicate a diagnosis of AD. © 2014 Japanese Society of Neuropathology.

  17. Alzheimer's disease: An alternative approach

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    Sadanandavalli Retnaswami Chandra

    2017-01-01

    Full Text Available Alzheimer's disease (AD is the most common neurodegenerative cortical dementia. It starts with memory loss, spatial disorientation in people above the age of 65 yr with a preference to females. Its incidence is expected to increase threefold by 2050. It affects almost one out of ten persons above the age of 65 years. Majority of patients are sporadic, but a very small percentage is autosomal dominant. The pathomechanisms postulated include amyloid cascade hypothesis according to which mutation in amyloid precursor protein causes Aβ aggregation. The next hypothesis is signal transducer and activation of transcription 3 (STAT3 causing aberration in intracellular signalling pathways. Senile plaques and neurofibrillary tangles are other important pathological changes reported. It is observed that dementia research has not yielded the expected result world over, and therefore, the pitfalls with reference to known facts about diagnosis, clinical features, pathogenic mechanisms, assessment of progression, biomarkers, treatment and prevention, as well as brief information on our experiments with relatively inexpensive methods of differentiating the most common types of dementia AD and frontotemporal dementia are discussed.

  18. Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease

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    van Duinen, S.G.; Castano, E.M.; Prelli, F.; Bots, G.T.A.B.; Luyendijk, W.; Frangione, B.

    1987-08-01

    Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related ..beta..-protein. Silver stain-positive, senile plaque-like structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from the leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approx. 4000 and its partial amino acid sequence to position 21 showed homology to the ..beta..-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of ..beta..-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.

  19. Quantification of neuropathological findings by image data for the diagnosis of dementia in forensic autopsy cases.

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    Takayama, Mio; Kashiwagi, Masayuki; Matsusue, Aya; Waters, Brian; Hara, Kenji; Ikematsu, Natsuki; Kubo, Shin-ichi

    2016-01-01

    The aim of the present study was to quantify neuropathological findings using image analysis software for the diagnosis of dementia in deceased who underwent forensic autopsy. Of the autopsies performed within 48 hours of death and excluding those of patients with head injury, thermal injury, heat stroke, or intracranial lesions, 8 were of autopsy cases clinically diagnosed with dementia and thus included in the dementia group (D). The non-dementia group (non-D) consisted of 6 deceased without dementia. To compare the D and non-D groups, 6 regions and 7 types of pathological findings were observed semi-quantitatively using 4 conventional stainings. Quantitative analysis of collected image data was performed using image analysis software. Semiquantitative analysis of senile plaques and neurofibrillary tangles was performed with Bielschowsky-Hirano's silver staining image data. An easy, simple, and effective quantification method of the pathological findings was achieved. However, no significant differences were observed between the two groups, and diagnosis of dementia by the quantification of pathological findings was not successful. Diagnosis of dementia using image data may be possible in future studies with an increased number of autopsies, and by utilizing staining techniques with higher specificity and sensitivity, such as immunohistochemical staining.

  20. The microglial NADPH oxidase complex as a source of oxidative stress in Alzheimer's disease

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    Landreth Gary E

    2006-11-01

    Full Text Available Abstract Alzheimer's disease is the most common cause of dementia in the elderly, and manifests as progressive cognitive decline and profound neuronal loss. The principal neuropathological hallmarks of Alzheimer's disease are the senile plaques and the neurofibrillary tangles. The senile plaques are surrounded by activated microglia, which are largely responsible for the proinflammatory environment within the diseased brain. Microglia are the resident innate immune cells in the brain. In response to contact with fibrillar beta-amyloid, microglia secrete a diverse array of proinflammatory molecules. Evidence suggests that oxidative stress emanating from activated microglia contribute to the neuronal loss characteristic of this disease. The source of fibrillar beta-amyloid induced reactive oxygen species is primarily the microglial nicotinamide adenine dinucleotide phosphate (NADPH oxidase. The NADPH oxidase is a multicomponent enzyme complex that, upon activation, produces the highly reactive free radical superoxide. The cascade of intracellular signaling events leading to NADPH oxidase assembly and the subsequent release of superoxide in fibrillar beta-amyloid stimulated microglia has recently been elucidated. The induction of reactive oxygen species, as well as nitric oxide, from activated microglia can enhance the production of more potent free radicals such as peroxynitrite. The formation of peroxynitrite causes protein oxidation, lipid peroxidation and DNA damage, which ultimately lead to neuronal cell death. The elimination of beta-amyloid-induced oxidative damage through the inhibition of the NADPH oxidase represents an attractive therapeutic target for the treatment of Alzheimer's disease.

  1. Pathophysiology of Alzheimer’s Disease

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    Mohammad Amani

    2017-01-01

    Full Text Available Alzheimer's disease (AD is a common cause of dementia in elderly people that is accompanied by progressive cognitive decline and memory loss. The pathologic hallmarks of AD are synaptic and neuronal degeneration together with extracellular senile plaques containing amyloid-beta (Aβ and the intracellular neurofibrillary tangles (NFTs in the hippocampus and other cortical regions. Amyloid-beta peptide is believed to have a pivotal role in the pathogenesis of AD as a major component of the senile plaques. It acts as a trigger key of AD and is considered as the principal toxic factor in the pathogenesis of the disease. Accumulation of amyloid β protein (Aβ, a main component of the senile plaques, in the brain initiates a cascade of events that ultimately lead to neuronal dysfunction and cognitive deficits. Other proposed mechanisms for AD include impairment in cholinergic function, oxidative stress, inflammatory agents and glutamate-mediated excitotoxicity. AD is characterized neuropathologically by impaired cholinergic function, increased oxidative stress, neuroinflammation, neuronal cell death, synapses loss, cortical atrophy, deficiencies in steroid hormones and appearance of glutamate-mediated excitotoxicity.

  2. A Systematic Review of Single Chinese Herbs for Alzheimer's Disease Treatment

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    Li-Min Fu

    2011-01-01

    Full Text Available The objectives here are to provide a systematic review of the current evidence concerning the use of Chinese herbs in the treatment of Alzheimer's disease (AD and to understand their mechanisms of action with respect to the pathophysiology of the disease. AD, characterized microscopically by deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, has become the most common cause of senile dementia. The limitations of western medications have led us to explore herbal medicine. In particular, many Chinese herbs have demonstrated some interesting therapeutic properties. The following databases were searched from their inception: MEDLINE (PUBMED, ALT HEALTH WATCH (EBSCO, CINAH and Cochrane Central. Only single Chinese herbs are included. Two reviewers independently extracted the data and performed quality assessment. The quality assessment of a clinical trial is based on the Jadad criteria. Seven Chinese herbs and six randomized controlled clinical trials were identified under the predefined criteria. Ginkgo biloba, Huperzine A (Lycopodium serratum and Ginseng have been assessed for their clinical efficacy with limited favorable evidence. No serious adverse events were reported. Chinese herbs show promise in the treatment of AD in terms of their cognitive benefits and more importantly, their mechanisms of action that deal with the fundamental pathophysiology of the disease. However, the current evidence in support of their use is inconclusive or inadequate. Future research should place emphasis on herbs that can treat the root of the disease.

  3. Aluminum access to the brain: A role for transferrin and its receptor

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    Roskams, A.J.; Connor, J.R. (Pennsylvania State Univ., Hershey (United States))

    1990-11-01

    The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer's disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer's disease. However, a mechanism for the entry of aluminum (Al{sup 3+}) into the cells of the central nervous system (CNS) has yet to be found. Here the authors describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe{sup 3}) aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.

  4. Ocular Manifestations of Alzheimer’s Disease in Animal Models

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    Miles Parnell

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is the most common form of dementia, and the pathological changes of senile plaques (SPs and neurofibrillary tangles (NFTs in AD brains are well described. Clinically, a diagnosis remains a postmortem one, hampering both accurate and early diagnosis as well as research into potential new treatments. Visual deficits have long been noted in AD patients, and it is becoming increasingly apparent that histopathological changes already noted in the brain also occur in an extension of the brain; the retina. Due to the optically transparent nature of the eye, it is possible to image the retina at a cellular level noninvasively and thus potentially allow an earlier diagnosis as well as a way of monitoring progression and treatment effects. Transgenic animal models expressing amyloid precursor protein (APP presenilin (PS and tau mutations have been used successfully to recapitulate the pathological findings of AD in the brain. This paper will cover the ocular abnormalities that have been detected in these transgenic AD animal models.

  5. Comparative analysis of the electroencephalogram in patients with Alzheimer's disease, diffuse axonal injury patients and healthy controls using LORETA analysis

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    Jéssica Natuline Ianof

    Full Text Available ABSTRACT Alzheimer's disease (AD is a dementia that affects a large contingent of the elderly population characterized by the presence of neurofibrillary tangles and senile plaques. Traumatic brain injury (TBI is a non-degenerative injury caused by an external mechanical force. One of the main causes of TBI is diffuse axonal injury (DAI, promoted by acceleration-deceleration mechanisms. Objective: To understand the electroencephalographic differences in functional mechanisms between AD and DAI groups. Methods: The study included 20 subjects with AD, 19 with DAI and 17 healthy adults submitted to high resolution EEG with 128 channels. Cortical sources of EEG rhythms were estimated by exact low-resolution electromagnetic tomography (eLORETA analysis. Results: The eLORETA analysis showed that, in comparison to the control (CTL group, the AD group had increased theta activity in the parietal and frontal lobes and decreased alpha 2 activity in the parietal, frontal, limbic and occipital lobes. In comparison to the CTL group, the DAI group had increased theta activity in the limbic, occipital sublobar and temporal areas. Conclusion: The results suggest that individuals with AD and DAI have impairment of electrical activity in areas important for memory and learning.

  6. Disease-modifying drugs in Alzheimer's disease

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    Ghezzi L

    2013-12-01

    Full Text Available Laura Ghezzi, Elio Scarpini, Daniela Galimberti Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy Abstract: Alzheimer's disease (AD is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, memantine, disease-modifying drugs, diagnosis, treatment

  7. Neuropathologic substrates of Parkinson disease dementia.

    Science.gov (United States)

    Irwin, David J; White, Matthew T; Toledo, Jon B; Xie, Sharon X; Robinson, John L; Van Deerlin, Vivianna; Lee, Virginia M-Y; Leverenz, James B; Montine, Thomas J; Duda, John E; Hurtig, Howard I; Trojanowski, John Q

    2012-10-01

    A study was undertaken to examine the neuropathological substrates of cognitive dysfunction and dementia in Parkinson disease (PD). One hundred forty patients with a clinical diagnosis of PD and either normal cognition or onset of dementia 2 or more years after motor symptoms (PDD) were studied. Patients with a clinical diagnosis of dementia with Lewy bodies were excluded. Autopsy records of genetic data and semiquantitative scores for the burden of neurofibrillary tangles, senile plaques, Lewy bodies (LBs), and Lewy neurites (LNs) and other pathologies were used to develop a multivariate logistic regression model to determine the independent association of these variables with dementia. Correlates of comorbid Alzheimer disease (AD) were also examined. Niney-two PD patients developed dementia, and 48 remained cognitively normal. Severity of cortical LB (CLB)/LN pathology was positively associated with dementia (p dementia in PD. Additionally, APOE4 genotype may independently influence the risk of dementia in PD. AD pathology was abundant in a subset of patients, and may modify the clinical phenotype. Thus, therapies that target α-synuclein, tau, or amyloid β could potentially improve cognitive performance in PD. Copyright © 2012 American Neurological Association.

  8. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease.

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    Helmfors, Linda; Boman, Andrea; Civitelli, Livia; Nath, Sangeeta; Sandin, Linnea; Janefjord, Camilla; McCann, Heather; Zetterberg, Henrik; Blennow, Kaj; Halliday, Glenda; Brorsson, Ann-Christin; Kågedal, Katarina

    2015-11-01

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease. Copyright © 2015. Published by Elsevier Inc.

  9. The heat shock/oxidative stress connection. Relevance to Alzheimer disease.

    Science.gov (United States)

    Pappolla, M A; Sos, M; Omar, R A; Sambamurti, K

    1996-01-01

    Involvement of free-radical oxidations in the aging process has been a topic of interest since Harman's original contribution. Because of the close association between aging and Alzheimer disease (AD) and the qualitative similarity in the neuropathology of both conditions, it has been proposed by many investigators that oxidative stress may be important in Ad. If such modality of injury was indeed involved, one should expect to find markers of oxidation and heat shock (since free radicals are key mediators of heat-shock induction) in brains of patients with AD. In fact, several studies documented abnormal expression of antioxidant enzymes and heat-shock proteins (HSP) along with other markers of oxidation in AD brains. We showed that abnormally expressed antioxidant enzymes are topographically associated with senile plaques and neurofibrillary tangles, and that the activity of these enzymes is (contrary to what one would expect) markedly reduced. These findings have recently been confirmed by other investigators. Despite a large amount of evidence that suggests an association between oxidative stress and the pathogenesis of AD, it is not yet known whether oxidative stress is a cause or consequence of the disorder. Future research efforts regarding the oxidative stress hypothesis of AD should include attempts at generating AD pathology by oxidative means in laboratory animals, determining the role and integrity of the heat-shock response in AD, as well as that of various antioxidant systems, growth factors, and hormones with antioxidant and neuroprotective properties.

  10. The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Filippo S. Giorgi

    2017-09-01

    Full Text Available Alzheimer’s Disease (AD features the accumulation of β-amyloid and Tau aggregates, which deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs, respectively. Neuronal Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem reticular formation and mostly within Locus Coeruleus (LC, which is consistently affected during AD. LC is the main source of forebrain norepinephrine (NE and it modulates a variety of functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal relationship between these events. In the present mini-review, we dedicate special emphasis to those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we considered which molecular mechanism may render these brainstem neurons so vulnerable.

  11. Can oral infection be a risk factor for Alzheimer's disease?

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    Olsen, Ingar; Singhrao, Sim K

    2015-01-01

    Alzheimer's disease (AD) is a scourge of longevity that will drain enormous resources from public health budgets in the future. Currently, there is no diagnostic biomarker and/or treatment for this most common form of dementia in humans. AD can be of early familial-onset or sporadic with a late-onset. Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia. To achieve the goal of finding a diagnostic biomarker and possible prophylactic treatment for AD, there is an initial need to solve the etiological puzzle contributing to its pathogenesis. This review therefore addresses oral infection as the plausible etiology of late-onset AD (LOAD).

  12. The novel beta-secretase inhibitor KMI-429 reduces amyloid beta peptide production in amyloid precursor protein transgenic and wild-type mice.

    Science.gov (United States)

    Asai, Masashi; Hattori, Chinatsu; Iwata, Nobuhisa; Saido, Takaomi C; Sasagawa, Noboru; Szabó, Beáta; Hashimoto, Yasuhiro; Maruyama, Kei; Tanuma, Sei-ichi; Kiso, Yoshiaki; Ishiura, Shoichi

    2006-01-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major component of the plaques, amyloid beta peptide (Abeta), is generated from amyloid precursor protein (APP) by beta- and gamma-secretase-mediated cleavage. Because beta-secretase/beta-site APP cleaving enzyme 1 (BACE1) knockout mice produce much less Abeta and grow normally, a beta-secretase inhibitor is thought to be one of the most attractive targets for the development of therapeutic interventions for AD without apparent side-effects. Here, we report the in vivo inhibitory effects of a novel beta-secretase inhibitor, KMI-429, a transition-state mimic, which effectively inhibits beta-secretase activity in cultured cells in a dose-dependent manner. We injected KMI-429 into the hippocampus of APP transgenic mice. KMI-429 significantly reduced Abeta production in vivo in the soluble fraction compared with vehicle, but the level of Abeta in the insoluble fraction was unaffected. In contrast, an intrahippocampal injection of KMI-429 in wild-type mice remarkably reduced Abeta production in both the soluble and insoluble fractions. Our results indicate that the beta-secretase inhibitor KMI-429 is a promising candidate for the treatment of AD.

  13. Methylene Blue Inhibits Caspases by Oxidation of the Catalytic Cysteine.

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    Pakavathkumar, Prateep; Sharma, Gyanesh; Kaushal, Vikas; Foveau, Bénédicte; LeBlanc, Andrea C

    2015-09-24

    Methylene blue, currently in phase 3 clinical trials against Alzheimer Disease, disaggregates the Tau protein of neurofibrillary tangles by oxidizing specific cysteine residues. Here, we investigated if methylene blue can inhibit caspases via the oxidation of their active site cysteine. Methylene blue, and derivatives, azure A and azure B competitively inhibited recombinant Caspase-6 (Casp6), and inhibited Casp6 activity in transfected human colon carcinoma cells and in serum-deprived primary human neuron cultures. Methylene blue also inhibited recombinant Casp1 and Casp3. Furthermore, methylene blue inhibited Casp3 activity in an acute mouse model of liver toxicity. Mass spectrometry confirmed methylene blue and azure B oxidation of the catalytic Cys163 cysteine of Casp6. Together, these results show a novel inhibitory mechanism of caspases via sulfenation of the active site cysteine. These results indicate that methylene blue or its derivatives could (1) have an additional effect against Alzheimer Disease by inhibiting brain caspase activity, (2) be used as a drug to prevent caspase activation in other conditions, and (3) predispose chronically treated individuals to cancer via the inhibition of caspases.

  14. Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy.

    Science.gov (United States)

    Lucke-Wold, Brandon P; Turner, Ryan C; Logsdon, Aric F; Nguyen, Linda; Bailes, Julian E; Lee, John M; Robson, Matthew J; Omalu, Bennet I; Huber, Jason D; Rosen, Charles L

    2016-03-01

    Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration. The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors' clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler. The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase-3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p chronic traumatic encephalopathy. Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.

  15. Alzheimer's disease: is a vaccine possible?

    Energy Technology Data Exchange (ETDEWEB)

    Alves, R.P.S. [Universidade de São Paulo, Instituto de Ciências Biomédicas II, Departamento de Microbiologia, Laboratório de Desenvolvimento de Vacinas, São Paulo, SP, Brasil, Laboratório de Desenvolvimento de Vacinas, Departamento de Microbiologia, Instituto de Ciências Biomédicas II, Universidade de São Paulo, São Paulo, SP (Brazil); Yang, M.J. [Instituto Butantan, Laboratório de Genética, São Paulo, SP, Brasil, Laboratório de Genética, Instituto Butantan, São Paulo, SP (Brazil); Batista, M.T.; Ferreira, L.C.S. [Universidade de São Paulo, Instituto de Ciências Biomédicas II, Departamento de Microbiologia, Laboratório de Desenvolvimento de Vacinas, São Paulo, SP, Brasil, Laboratório de Desenvolvimento de Vacinas, Departamento de Microbiologia, Instituto de Ciências Biomédicas II, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-05-09

    The cause of Alzheimer's disease is still unknown, but the disease is distinctively characterized by the accumulation of β-amyloid plaques and neurofibrillary tangles in the brain. These features have become the primary focus of much of the research looking for new treatments for the disease, including immunotherapy and vaccines targeting β-amyloid in the brain. Adverse effects observed in a clinical trial based on the β-amyloid protein were attributed to the presence of the target antigen and emphasized the relevance of finding safer antigen candidates for active immunization. For this kind of approach, different vaccine formulations using DNA, peptide, and heterologous prime-boost immunization regimens have been proposed. Promising results are expected from different vaccine candidates encompassing B-cell epitopes of the β-amyloid protein. In addition, recent results indicate that targeting another protein involved in the etiology of the disease has opened new perspectives for the effective prevention of the illness. Collectively, the evidence indicates that the idea of finding an effective vaccine for the control of Alzheimer's disease, although not without challenges, is a possibility.

  16. DYRK1A genetic variants are not linked to Alzheimer's disease in a Spanish case-control cohort

    Directory of Open Access Journals (Sweden)

    Berciano José

    2009-12-01

    Full Text Available Abstract Background As dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A has been implicated in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD brain, and the development of neurofibrillary tangles, we examined the contribution of this gene to the susceptibility for AD. Methods We examined genetic variations of DYRK1A by genotyping haplotype tagging SNPs (htSNPs (rs11701483, rs2835740, rs1137600, rs2835761, rs2835762, rs2154545 and rs8132976 in a group of 634 Spanish AD cases and 733 controls. Results There were no differences in the genotypic, allelic or haplotypic distributions between cases and controls in the overall analysis or after stratification by APOE ε4 allele. Conclusion Our negative findings in the Spanish population argue against the hypothesis that DYRK1A genetic variations are causally related to AD risk. Still, additional studies using different sets of patients and control subjects deserve further attention, since supporting evidence for association between DYRK1A gene and AD risk in the Japanese population exists.

  17. The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes.

    Science.gov (United States)

    Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Dia