WorldWideScience

Sample records for amyloid plaque pathogenesis

  1. MR Microimaging of amyloid plaques in Alzheimer's disease transgenic mice

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is the most prevalent neurological condition affecting industrialized nations and will rapidly become a healthcare crisis as the population ages. Currently, the post-mortem histological observation of amyloid plaques and neurofibrillary tangles is the only definitive diagnosis available for AD. A pre-mortem biological or physiological marker specific for AD used in conjunction with current neurological and memory testing could add a great deal of confidence to the diagnosis of AD and potentially allow therapeutic intervention much earlier in the disease process. Our group has developed MRI techniques to detect individual amyloid plaques in AD transgenic mouse brain in vivo. We are also developing contrast-enhancing agents to increase the specificity of detection of amyloid plaques. Such in vivo imaging of amyloid plaques will also allow the evaluation of anti-amyloid therapies being developed by the pharmaceutical industry in pre-clinical trials of AD transgenic mice. This short review briefly discusses our progress in these areas. (orig.)

  2. Amyloid Plaques in PSAPP Mice Bind Less Metal than Plaques in Human Alzheimer's Disease

    International Nuclear Information System (INIS)

    Amyloid beta (AΒ) is the primary component of Alzheimer's disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N = 6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal binding to Aβ is thought to induce redox chemistry that is toxic to neurons, the reduced metal binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology.

  3. Amyloid plaque imaging in vivo: current achievement and future prospects

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is a very complex neurodegenerative disorder, the exact cause of which is still not known. The major histopathological features, amyloid plaques and neurofibrillary tangles, already described by Alois Alzheimer, have been the focus in research for decades. Despite a probable whole cascade of events in the brain leading to impairment of cognition, amyloid is still the target for diagnosis and treatment. The rapid development of molecular imaging techniques now allows imaging of amyloid plaques in vivo in Alzheimer patients by PET amyloid ligands such as Pittsburgh compound B (PIB). Studies so far have revealed high 11C-PIB retention in brain at prodromal stages of AD and a possibility to discriminate AD from other dementia disorders by 11C-PIB. Ongoing studies are focussing to understand the relationship between brain and CSF amyloid processes and cognitive processes. In vivo imaging of amyloid will be important for early diagnosis and evaluation of new anti-amyloid therapies in AD. (orig.)

  4. Amyloid-plaque imaging in diagnosis of dementia

    International Nuclear Information System (INIS)

    The increasing life-expectancy of our society results in a continuously growing number of patients suffering from dementing disorders, particularly Alzheimer's disease (AD). Apart from the deleterious consequences for the patients and their relatives, this has also alarming effects on our social systems. These facts have justified increased scientific efforts regarding the identification of basic pathomechanisms of dementia and the development of new treatment options. Increased production of specific proteins and their pathologic aggregation in the brain appears to be a pathomechanism which occurs early in the course of many different neurodegenerative disorders. Among the most well-known of these protein aggregations are the amyloid-plaques, which arise from the aggregation of the β-amyloid protein. Currently, this amyloid-aggregation pathology is regarded as a key pathology, playing a causal role in the development of AD. Consequently, modern therapy approaches are directed towards this target. Limited access to brain tissue has so far restricted the definite diagnosis of AD to post mortem histopathological assessment of brain tissue. For the same reason, a clear association between extent of amyloid deposition pathology and clinical course of AD has not been established so far. However, particularly with regard to new therapeutic options a reliable in vivo diagnosis is required. Modern molecular imaging tracers such as [11C]PIB do now open the possibility to visualize amyloid-depositions in vivo, using Positron Emission Tomography (PET). These techniques allow the characterization of dementing disorders on the basis of the underlying pathology rather than on their symptomatic appearance. This type of ''in vivo histopathology''-approach may offer improved options for early and differential diagnosis, as well as for patient selection for therapy trials and for objective therapy monitoring. (orig.)

  5. Detection of Alzheimer’s disease amyloid-beta plaque deposition by deep brain impedance profiling

    Science.gov (United States)

    Béduer, Amélie; Joris, Pierre; Mosser, Sébastien; Fraering, Patrick C.; Renaud, Philippe

    2015-04-01

    Objective. Alzheimer disease (AD) is the most common form of neurodegenerative disease in elderly people. Toxic brain amyloid-beta (Aß) aggregates and ensuing cell death are believed to play a central role in the pathogenesis of the disease. In this study, we investigated if we could monitor the presence of these aggregates by performing in situ electrical impedance spectroscopy measurements in AD model mice brains. Approach. In this study, electrical impedance spectroscopy measurements were performed post-mortem in APPPS1 transgenic mice brains. This transgenic model is commonly used to study amyloidogenesis, a pathological hallmark of AD. We used flexible probes with embedded micrometric electrodes array to demonstrate the feasibility of detecting senile plaques composed of Aß peptides by localized impedance measurements. Main results. We particularly focused on deep brain structures, such as the hippocampus. Ex vivo experiments using brains from young and old APPPS1 mice lead us to show that impedance measurements clearly correlate with the percentage of Aβ plaque load in the brain tissues. We could monitor the effects of aging in the AD APPPS1 mice model. Significance. We demonstrated that a localized electrical impedance measurement constitutes a valuable technique to monitor the presence of Aβ-plaques, which is complementary with existing imaging techniques. This method does not require prior Aβ staining, precluding the risk of variations in tissue uptake of dyes or tracers, and consequently ensuring reproducible data collection.

  6. Augmented Senile Plaque Load in Aged Female β-Amyloid Precursor Protein-Transgenic Mice

    OpenAIRE

    Callahan, Michael J.; Lipinski, William J.; Bian, Feng; Durham, Robert A.; Pack, Amy; Walker, Lary C.

    2001-01-01

    Transgenic mice (Tg2576) overexpressing human β-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer’s disease-like amyloid β protein (Aβ) deposits by 8 to 10 months of age. These mice show elevated levels of Aβ40 and Aβ42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased m...

  7. Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models

    International Nuclear Information System (INIS)

    Amyloidplaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (<50 μm diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs).

  8. In vivo detection of amyloid plaques by gadolinium-stained MRI can be used to demonstrate the efficacy of an anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Mathieu D. Santin

    2016-03-01

    Full Text Available Extracellular deposition of β amyloid plaques is an early event associated to Alzheimer's disease. Here we have used in vivo gadolinium-stained high resolution (29*29*117µm3 MRI to follow-up in a longitudinal way individual amyloid plaques in APP/PS1 mice and evaluate the efficacy of a new immunotherapy (SAR255952 directed against protofibrillar and fibrillary forms of Aβ. APP/PS1 mice were treated for 5 months between the age of 3.5 and 8.5 months. SAR255952 reduced amyloid load in 8.5-month-old animals, but not in 5.5-month animals compared to mice treated with a control antibody (DM4. Histological evaluation confirmed the reduction of amyloid load and revealed a lower density of amyloid plaques in 8.5-month SAR255952-treated animals. The longitudinal follow-up of individual amyloid plaques by MRI revealed that plaques that were visible at 5.5 months were still visible at 8.5 months in both SAR255952 and DM4-treated mice. This suggests that the amyloid load reduction induced by SAR255952 is related to a slowing down in the formation of new plaques rather than to the clearance of already formed plaques.

  9. Characterization of IMPY as a potential imaging agent for β-amyloid plaques in double transgenic PSAPP mice

    International Nuclear Information System (INIS)

    Deposition of β-amyloid (Aβ) plaques in the brain is likely linked to the pathogenesis of Alzheimer's disease (AD). Developing specific Aβ aggregate-binding ligands as in vivo imaging agents may be useful for diagnosis and monitoring the progression of AD. We have prepared a thioflavin derivative, 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridine, IMPY, which is readily radiolabeled with 125I/123I for binding or single-photon emission computerized tomography (SPECT) imaging studies. Characterization of [125I]IMPY binding to plaque-like structures was evaluated in double transgenic PSAPP mice. [125I]IMPY labeled Aβ plaques in transgenic mouse brain sections, and the labeling was consistent with fluorescent staining and Aβ-specific antibody labeling. Significant amounts of Aβ plaques present in the cortical, hippocampal, and entorhinal regions of the transgenic mouse brain were clearly detected with [125I]IMPY via ex vivo autoradiography. In contrast, [125I]IMPY showed little labeling in the age-matched control mouse brain. Tissue homogenate binding further corroborated the Aβ plaque-specific distribution in various brain regions of transgenic mouse, and correlated well with the known density of Aβ deposition. Using a tissue dissection technique, [125I]IMPY showed a moderate increase in the cortical region of transgenic mice as compared to the age-matched controls. In vitro blocking of [125I]IMPY by ''carrier'' observed via autoradiography in mouse brain sections was not replicated by an in vivo blocking experiment in living TT mouse brain. The failure was most likely due to a significant carrier effect, which slows down the tracer in vivo metabolism, leading to an increased brain uptake. Taken together, these data indicate that [123I]IMPY is a potentially useful SPECT imaging agent for in vivo labeling of Aβ plaques in the living brain. (orig.)

  10. Identification of Amyloid Plaques in Retinas from Alzheimer’s Patients and Noninvasive In Vivo Optical Imaging of Retinal Plaques in a Mouse Model

    OpenAIRE

    Koronyo-Hamaoui, Maya; Koronyo, Yosef; Ljubimov, Alexander V.; Miller, Carol A.; Ko, MinHee K; Keith L. Black; Schwartz, Michal; Farkas, Daniel L.

    2010-01-01

    Noninvasive monitoring of β-amyloid (Aβ) plaques, the neuropathological hallmarks of Alzheimer's disease (AD), is critical for AD diagnosis and prognosis. Current visualization of Aβ plaques in brains of live patients and animal models is limited in specificity and resolution. The retina as an extension of the brain portrays an appealing target for a live, noninvasive optical imaging of AD if disease pathology is manifested there. We identified retinal Aβ plaques in postmortem eyes from AD pa...

  11. Inhibition of amyloidplaque formation by α-synuclein.

    Science.gov (United States)

    Bachhuber, Teresa; Katzmarski, Natalie; McCarter, Joanna F; Loreth, Desiree; Tahirovic, Sabina; Kamp, Frits; Abou-Ajram, Claudia; Nuscher, Brigitte; Serrano-Pozo, Alberto; Müller, Alexandra; Prinz, Marco; Steiner, Harald; Hyman, Bradley T; Haass, Christian; Meyer-Luehmann, Melanie

    2015-07-01

    Amyloid-β (Aβ) plaques and α-synuclein (α-syn)-rich Lewy bodies are the major neuropathological hallmarks of Alzheimer's disease (AD) and Parkinson's disease, respectively. An overlap of pathologies is found in most individuals with dementia with Lewy bodies (DLB) and in more than 50% of AD cases. Their brains display substantial α-syn accumulation not only in Lewy bodies, but also in dystrophic neurites decorating Aβ plaques. Several studies report binding and coaggregation of Aβ and α-syn, yet the precise role of α-syn in amyloid plaque formation remains elusive. Here we performed intracerebral injections of α-syn-containing preparations into amyloid precursor protein (APP) transgenic mice (expressing APP695(KM670/671NL) and PSEN1(L166P) under the control of the neuron-specific Thy-1 promoter; referred to here as 'APPPS1'). Unexpectedly, α-syn failed to cross-seed Aβ plaques in vivo, but rather it inhibited plaque formation in APPPS1 mice coexpressing SNCA(A30P) (referred to here as 'APPPS1 × [A30P]aSYN' double-transgenic mice). This was accompanied by increased Aβ levels in cerebrospinal fluid despite unchanged overall Aβ levels. Notably, the seeding activity of Aβ-containing brain homogenates was considerably reduced by α-syn, and Aβ deposition was suppressed in grafted tissue from [A30P]aSYN transgenic mice. Thus, we conclude that an interaction between Aβ and α-syn leads to inhibition of Aβ deposition and to reduced plaque formation. PMID:26099047

  12. Polarization properties of amyloid-beta plaques in Alzheimer's disease (Conference Presentation)

    Science.gov (United States)

    Baumann, Bernhard; Wöhrer, Adelheid; Ricken, Gerda; Pircher, Michael; Kovacs, Gabor G.; Hitzenberger, Christoph K.

    2016-03-01

    In histopathological practice, birefringence is used for the identification of amyloidosis in numerous tissues. Amyloid birefringence is caused by the parallel arrangement of fibrous protein aggregates. Since neurodegenerative processes in Alzheimer's disease (AD) are also linked to the formation of amyloid-beta (Aβ) plaques, optical methods sensitive to birefringence may act as non-invasive tools for Aβ identification. At last year's Photonics West, we demonstrated polarization-sensitive optical coherence tomography (PS-OCT) imaging of ex vivo cerebral tissue of advanced stage AD patients. PS-OCT provides volumetric, structural imaging based on both backscatter contrast and tissue polarization properties. In this presentation, we report on polarization-sensitive neuroimaging along with numerical simulations of three-dimensional Aβ plaques. High speed PS-OCT imaging was performed using a spectral domain approach based on polarization maintaining fiber optics. The sample beam was interfaced to a confocal scanning microscope arrangement. Formalin-fixed tissue samples as well as thin histological sections were imaged. For comparison to the PS-OCT results, ray propagation through plaques was modeled using Jones analysis and various illumination geometries and plaque sizes. Characteristic polarization patterns were found. The results of this study may not only help to understand PS-OCT imaging of neuritic Aβ plaques but may also have implications for polarization-sensitive imaging of other fibrillary structures.

  13. Polyfluorinated bis-styrylbenzenes as amyloidplaque binding ligands.

    Science.gov (United States)

    Nabuurs, Rob J A; Kapoerchan, Varsha V; Metaxas, Athanasios; de Jongh, Sanne; de Backer, Maaike; Welling, Mick M; Jiskoot, Wim; Windhorst, Albert D; Overkleeft, Hermen S; van Buchem, Mark A; Overhand, Mark; van der Weerd, Louise

    2014-04-15

    Detection of cerebral β-amyloid (Aβ) by targeted contrast agents remains of great interest to aid the in vivo diagnosis of Alzheimer's disease (AD). Bis-styrylbenzenes have been previously reported as potential Aβ imaging agents. To further explore their potency as (19)F MRI contrast agents we synthetized several novel fluorinated bis-styrylbenzenes and studied their fluorescent properties and amyloid-β binding characteristics. The compounds showed a high affinity for Aβ plaques on murine and human brain sections. Interestingly, competitive binding experiments demonstrated that they bound to a different binding site than chrysamine G. Despite their high logP values, many bis-styrylbenzenes were able to enter the brain and label murine amyloid in vivo. Unfortunately initial post-mortem (19)F NMR studies showed that these compounds as yet do not warrant further MRI studies due to the reduction of the (19)F signal in the environment of the brain. PMID:24657049

  14. Amyloid-plaque imaging in early and differential diagnosis of dementia

    International Nuclear Information System (INIS)

    The increasing life expectancy in our society results in a continuously growing number of patients suffering from neurodegenerative disorders, particularly Alzheimer's disease (AD). Apart from the deleterious consequences for patients and their relatives, this issue has also alarming effects on our social systems. These facts have justified increased scientific efforts regarding the identification of basic pathomechanisms of dementia and the development of new treatment options. Increased production of specific proteins and their pathologic aggregation in the brain appears to be a pathomechanism which occurs early in the course of many different neurodegenerative diseases. Among the most well-known of these protein aggregations are amyloid plaques, which arise from the aggregation of the β-amyloid protein. Currently, this amyloid-aggregation pathology is regarded as a key pathology, playing a causal role in the development of AD. Consequently, modern therapy approaches are directed towards this target. Limited access to brain tissue has so far restricted the definite diagnosis of AD to postmortem histopathological assessment of brain tissue. For the same reason, a clear association between extent of amyloid deposition pathology and clinical course of AD has not been established so far. However, particularly with regard to new therapeutic options, a reliable in vivo diagnosis is required. Modern molecular imaging tracers such as [11C]Pittsburgh Compound B (PIB) do now open the possibility to visualize amyloid depositions in vivo, using positron emission tomography. This type of ''in vivo histopathology'' approach allows the characterization of neurodegenerative disorders on the basis of the underlying pathology rather than on their symptomatic appearance. In this manuscript, we will discuss the options of amyloid-plaque imaging regarding early and differential diagnosis of different forms of dementia as well as for patient selection for therapy trials and for

  15. [18F]Fluoroazabenzoxazoles as potential amyloid plaque PET tracers: synthesis and in vivo evaluation in rhesus monkey

    International Nuclear Information System (INIS)

    Introduction: An 18F-labeled positron emission tomography (PET) tracer for amyloid plaque is desirable for early diagnosis of Alzheimer's disease, particularly to enable preventative treatment once effective therapeutics are available. Similarly, such a tracer would be useful as a biomarker for enrollment of patients in clinical trials for evaluation of antiamyloid therapeutics. Furthermore, changes in the level of plaque burden as quantified by an amyloid plaque PET tracer may provide valuable insights into the effectiveness of amyloid-targeted therapeutics. This work describes our approach to evaluate and select a candidate PET tracer for in vivo quantification of human amyloid plaque. Methods: Ligands were evaluated for their in vitro binding to human amyloid plaques, lipophilicity and predicted blood–brain barrier permeability. Candidates with favorable in vitro properties were radiolabeled with 18F and evaluated in vivo. Baseline PET scans in rhesus monkey were conducted to evaluate the regional distribution and kinetics of each tracer using tracer kinetic modeling methods. High binding potential in cerebral white matter and cortical grey matter was considered an unfavorable feature of the candidate tracers. Results: [18F]MK-3328 showed the most favorable combination of low in vivo binding potential in white matter and cortical grey matter in rhesus monkeys, low lipophilicity (Log D=2.91) and high affinity for human amyloid plaques (IC50=10.5±1.3 nM). Conclusions: [18F]MK-3328 was identified as a promising PET tracer for in vivo quantification of amyloid plaques, and further evaluation in humans is warranted.

  16. Nanoparticulate Radiolabelled Quinolines Detect Amyloid Plaques in Mouse Models of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Frederick J. Bonte

    2009-01-01

    Full Text Available Detecting aggregated amyloid peptides (Aβ plaques presents targets for developing biomarkers of Alzheimer's disease (AD. Polymeric n-butyl-2-cyanoacrylate (PBCA nanoparticles (NPs were encapsulated with radiolabelled amyloid affinity I125-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline as in vivo probes. I125-CQ-PBCA NPs crossed the BBB (2.3±0.9 ID/g (P<.05 in the WT mouse (N = 210, compared to I125-CQ (1.0±0.4 ID/g. I125-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1 versus WT (N = 38; 2.54×105±5.31×104 DLU/mm2; versus 1.98×105±2.22×104 DLU/mm2 and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Aβ42 peptide (N = 17; 7.19×105±1.25×105 DLU/mm2, versus WT (6.07×105±7.47×104 DLU/mm2. Storage phosphor imaging and histopathological staining of the plaques, Fe2+ and Cu2+, validated results. I125-CQ-PBCA NPs have specificity for Aβ in vitro and in vivo and are promising as in vivo SPECT (I123, or PET (I124 amyloid imaging agents.

  17. In vivo detection of prion amyloid plaques using [11C]BF-227 PET

    International Nuclear Information System (INIS)

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [11C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [11C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  18. In vivo detection of prion amyloid plaques using [{sup 11}C]BF-227 PET

    Energy Technology Data Exchange (ETDEWEB)

    Okamura, Nobuyuki; Yanai, Kazuhiko [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Shiga, Yusei; Itoyama, Yasuhito [Tohoku University School of Medicine, Department of Neurology, Sendai (Japan); Furumoto, Shozo [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan); Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Tashiro, Manabu [Tohoku University, Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Sendai (Japan); Tsuboi, Yoshio [Fukuoka University School of Medicine, Department of Neurology, Fukuoka (Japan); Furukawa, Katsutoshi; Arai, Hiroyuki [Institute of Development, Aging, and Cancer, Tohoku University, Department of Geriatrics and Gerontology, Division of Brain Sciences, Sendai (Japan); Iwata, Ren [Tohoku University, Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Sendai (Japan); Kudo, Yukitsuka [Tohoku University, Innovation of New Biomedical Engineering Center, Sendai (Japan); Doh-ura, Katsumi [Tohoku University School of Medicine, Department of Prion Research, 2-1 Seiryo-machi, Aoba-ku, Sendai (Japan)

    2010-05-15

    In vivo detection of pathological prion protein (PrP) in the brain is potentially useful for the diagnosis of transmissible spongiform encephalopathies (TSEs). However, there are no non-invasive ante-mortem means for detection of pathological PrP deposition in the brain. The purpose of this study is to evaluate the amyloid imaging tracer BF-227 with positron emission tomography (PET) for the non-invasive detection of PrP amyloid in the brain. The binding ability of BF-227 to PrP amyloid was investigated using autoradiography and fluorescence microscopy. Five patients with TSEs, including three patients with Gerstmann-Straeussler-Scheinker disease (GSS) and two patients with sporadic Creutzfeldt-Jakob disease (CJD), underwent [{sup 11}C]BF-227 PET scans. Results were compared with data from 10 normal controls and 17 patients with Alzheimer's disease (AD). The regional to pons standardized uptake value ratio was calculated as an index of BF-227 retention. Binding of BF-227 to PrP plaques was confirmed using brain samples from autopsy-confirmed GSS cases. In clinical PET study, significantly higher retention of BF-227 was detected in the cerebellum, thalamus and lateral temporal cortex of GSS patients compared to that in the corresponding tissues of normal controls. GSS patients also showed higher retention of BF-227 in the cerebellum, thalamus and medial temporal cortex compared to AD patients. In contrast, the two CJD patients showed no obvious retention of BF-227 in the brain. Although [{sup 11}C]BF-227 is a non-specific imaging marker of cerebral amyloidosis, it is useful for in vivo detection of PrP plaques in the human brain in GSS, based on the regional distribution of the tracer. PET amyloid imaging might provide a means for both early diagnosis and non-invasive disease monitoring of certain forms of TSEs. (orig.)

  19. Correlative Light and Electron Microscopy to Study Microglial Interactions with β-Amyloid Plaques.

    Science.gov (United States)

    Bisht, Kanchan; El Hajj, Hassan; Savage, Julie C; Sánchez, Maria G; Tremblay, Marie-Ève

    2016-01-01

    A detailed protocol is provided here to identify amyloidplaques in brain sections from Alzheimer's disease mouse models before pre-embedding immunostaining (specifically for ionized calcium-binding adapter molecule 1 (IBA1), a calcium binding protein expressed by microglia) and tissue processing for electron microscopy (EM). Methoxy-X04 is a fluorescent dye that crosses the blood-brain barrier and selectively binds to β-pleated sheets found in dense core Aβ plaques. Injection of the animals with methoxy-X04 prior to sacrifice and brain fixation allows pre-screening and selection of the plaque-containing brain sections for further processing with time-consuming manipulations. This is particularly helpful when studying early AD pathology within specific brain regions or layers that may contain very few plaques, present in only a small fraction of the sections. Post-mortem processing of tissue sections with Congo Red, Thioflavin S, and Thioflavin T (or even with methoxy-X04) can label β-pleated sheets, but requires extensive clearing with ethanol to remove excess dye and these procedures are incompatible with ultrastructural preservation. It would also be inefficient to perform labeling for Aβ (and other cellular markers such as IBA1) on all brain sections from the regions of interest, only to yield a small fraction containing Aβ plaques at the right location. Importantly, Aβ plaques are still visible after tissue processing for EM, allowing for a precise identification of the areas (generally down to a few square millimeters) to examine with the electron microscope. PMID:27286292

  20. Amyloid-plaque imaging in diagnosis of dementia; Amyloidplaque-Bildgebung in der Demenzdiagnostik

    Energy Technology Data Exchange (ETDEWEB)

    Drzezga, A. [Klinikum rechts der Isar, Technische Univ. Muenchen (Germany). Nuklearmedizinische Klinik

    2009-06-15

    The increasing life-expectancy of our society results in a continuously growing number of patients suffering from dementing disorders, particularly Alzheimer's disease (AD). Apart from the deleterious consequences for the patients and their relatives, this has also alarming effects on our social systems. These facts have justified increased scientific efforts regarding the identification of basic pathomechanisms of dementia and the development of new treatment options. Increased production of specific proteins and their pathologic aggregation in the brain appears to be a pathomechanism which occurs early in the course of many different neurodegenerative disorders. Among the most well-known of these protein aggregations are the amyloid-plaques, which arise from the aggregation of the {beta}-amyloid protein. Currently, this amyloid-aggregation pathology is regarded as a key pathology, playing a causal role in the development of AD. Consequently, modern therapy approaches are directed towards this target. Limited access to brain tissue has so far restricted the definite diagnosis of AD to post mortem histopathological assessment of brain tissue. For the same reason, a clear association between extent of amyloid deposition pathology and clinical course of AD has not been established so far. However, particularly with regard to new therapeutic options a reliable in vivo diagnosis is required. Modern molecular imaging tracers such as [{sup 11}C]PIB do now open the possibility to visualize amyloid-depositions in vivo, using Positron Emission Tomography (PET). These techniques allow the characterization of dementing disorders on the basis of the underlying pathology rather than on their symptomatic appearance. This type of ''in vivo histopathology''-approach may offer improved options for early and differential diagnosis, as well as for patient selection for therapy trials and for objective therapy monitoring. (orig.)

  1. Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of β-amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for β-amyloid (Aβ) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for Aβ1-42 aggregates (Ki=9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [125I]12, labeled Aβ plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [125I]12 showed high uptake [4.14 percent injected dose per gram (% ID/g) at 2 min] into and rapid clearance (0.15% ID/g at 60 min) from the brain, which may bring about a good signal-to-noise ratio and therefore achieve highly sensitive detection of Aβ plaques. In addition, [125I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [125I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with 123I, it may be a useful SPECT imaging agent for Aβ plaques in the brain of living AD patients.

  2. Type II fuzzy systems for amyloid plaque segmentation in transgenic mouse brains for Alzheimer's disease quantification

    Science.gov (United States)

    Khademi, April; Hosseinzadeh, Danoush

    2014-03-01

    Alzheimer's disease (AD) is the most common form of dementia in the elderly characterized by extracellular deposition of amyloid plaques (AP). Using animal models, AP loads have been manually measured from histological specimens to understand disease etiology, as well as response to treatment. Due to the manual nature of these approaches, obtaining the AP load is labourious, subjective and error prone. Automated algorithms can be designed to alleviate these challenges by objectively segmenting AP. In this paper, we focus on the development of a novel algorithm for AP segmentation based on robust preprocessing and a Type II fuzzy system. Type II fuzzy systems are much more advantageous over the traditional Type I fuzzy systems, since ambiguity in the membership function may be modeled and exploited to generate excellent segmentation results. The ambiguity in the membership function is defined as an adaptively changing parameter that is tuned based on the local contrast characteristics of the image. Using transgenic mouse brains with AP ground truth, validation studies were carried out showing a high degree of overlap and low degree of oversegmentation (0.8233 and 0.0917, respectively). The results highlight that such a framework is able to handle plaques of various types (diffuse, punctate), plaques with varying Aβ concentrations as well as intensity variation caused by treatment effects or staining variability.

  3. Computed tomography of amyloid plaques in a mouse model of Alzheimers disease using diffraction enhanced imaging

    Energy Technology Data Exchange (ETDEWEB)

    Connor, D.M.; Miller, L.; Benveniste, H.; Dilmanian, A.; Kritzer, M.; Zhong, Z.

    2009-03-19

    Our understanding of early development in Alzheimer's disease (AD) is clouded by the scale at which the disease progresses; amyloid beta (A{beta}) plaques, a hallmark feature of AD, are small ({approx} 50 {micro}m) and low contrast in diagnostic clinical imaging techniques. Diffraction enhanced imaging (DEI), a phase contrast x-ray imaging technique, has greater soft tissue contrast than conventional radiography and generates higher resolution images than magnetic resonance microimaging. Thus, in this proof of principle study, DEI in micro-CT mode was performed on the brains of AD-model mice to determine if DEI can visualize A{beta} plaques. Results revealed small nodules in the cortex and hippocampus of the brain. Histology confirmed that the features seen in the DEI images of the brain were A{beta} plaques. Several anatomical structures, including hippocampal subregions and white matter tracks, were also observed. Thus, DEI has strong promise in early diagnosis of AD, as well as general studies of the mouse brain.

  4. Synthesis and evaluation of ethyleneoxylated and allyloxylated chalcone derivatives for imaging of amyloid β plaques by SPECT

    OpenAIRE

    Fuchigami, Takeshi; Yamashita, Yuki; Haratake, Mamoru; Ono, Masahiro; Yoshida, Sakura; Nakayama, Morio

    2014-01-01

    We report radioiodinated chalcone derivatives as new SPECT imaging probes for amyloid β (Aβ) plaques. The monoethyleneoxy derivative 2 and allyloxy derivative 8 showed a high affinity for Aβ(1-42) aggregates with Ki values of 24 and 4.5 nM, respectively. Fluorescent imaging demonstrated that 2 and 8 clearly stained thioflavin-S positive Aβ plaques in the brain sections of Tg2576 transgenic mice. In vitro autoradiography revealed that [125I]2 displayed no clear accumulation toward Aβ plaques i...

  5. RNA aptamer probes as optical imaging agents for the detection of amyloid plaques.

    Directory of Open Access Journals (Sweden)

    Christian T Farrar

    Full Text Available Optical imaging using multiphoton microscopy and whole body near infrared imaging has become a routine part of biomedical research. However, optical imaging methods rely on the availability of either small molecule reporters or genetically encoded fluorescent proteins, which are challenging and time consuming to develop. While directly labeled antibodies can also be used as imaging agents, antibodies are species specific, can typically not be tagged with multiple fluorescent reporters without interfering with target binding, and are bioactive, almost always eliciting a biological response and thereby influencing the process that is being studied. We examined the possibility of developing highly specific and sensitive optical imaging agents using aptamer technology. We developed a fluorescently tagged anti-Aβ RNA aptamer, β55, which binds amyloid plaques in both ex vivo human Alzheimer's disease brain tissue and in vivo APP/PS1 transgenic mice. Diffuse β55 positive halos, attributed to oligomeric Aβ, were observed surrounding the methoxy-XO4 positive plaque cores. Dot blots of synthetic Aβ aggregates provide further evidence that β55 binds both fibrillar and non-fibrillar Aβ. The high binding affinity, the ease of probe development, and the ability to incorporate multiple and multimodal imaging reporters suggest that RNA aptamers may have complementary and perhaps advantageous properties compared to conventional optical imaging probes and reporters.

  6. Synthesis and evaluation of 18F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [11C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of 11C, longer lived 18F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [18F]fluoroethoxy-substituted benzothiazole derivatives ([18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [18F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [18F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [18F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [18F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [18F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  7. Effect of catalpol on senile plaques and spatial learning and memory ability in amyloid-β protein precursor/presenilin 1 double transgenic mice

    Institute of Scientific and Technical Information of China (English)

    宋冲

    2013-01-01

    Objective To investigate whether catalpol affects senile plaque formation and spatial learning and memory ability in the amyloid-βprotein precursor/presenilin 1(APP/PS1)double transgenic mice.Methods

  8. Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI).

    Science.gov (United States)

    Cheng, Kwok Kin; Chan, Pui Shan; Fan, Shujuan; Kwan, Siu Ming; Yeung, King Lun; Wáng, Yì-Xiáng J; Chow, Albert Hee Lum; Wu, Ed X; Baum, Larry

    2015-03-01

    Diagnosis of Alzheimer's disease (AD) can be performed with the assistance of amyloid imaging. The current method relies on positron emission tomography (PET), which is expensive and exposes people to radiation, undesirable features for a population screening method. Magnetic resonance imaging (MRI) is cheaper and is not radioactive. Our approach uses magnetic nanoparticles (MNPs) made of superparamagnetic iron oxide (SPIO) conjugated with curcumin, a natural compound that specifically binds to amyloid plaques. Coating of curcumin-conjugated MNPs with polyethylene glycol-polylactic acid block copolymer and polyvinylpyrrolidone by antisolvent precipitation in a multi-inlet vortex mixer produces stable and biocompatible curcumin magnetic nanoparticles (Cur-MNPs) with mean diameter microscopy and atomic force microscopy, and their structure and chemistry were further characterized by X-ray diffraction, thermogravimetric analysis, X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectrometry, and Fourier transform infrared spectroscopy. Cur-MNPs exhibited no cytotoxicity in either Madin-Darby canine kidney (MDCK) or differentiated human neuroblastoma cells (SH-SY5Y). The Papp of Cur-MNPs was 1.03 × 10(-6) cm/s in an in vitro blood-brain barrier (BBB) model. Amyloid plaques could be visualized in ex vivo T2*-weighted magnetic resonance imaging (MRI) of Tg2576 mouse brains after injection of Cur-MNPs, and no plaques could be found in non-transgenic mice. Immunohistochemical examination of the mouse brains revealed that Cur-MNPs were co-localized with amyloid plaques. Thus, Cur-MNPs have the potential for non-invasive diagnosis of AD using MRI. PMID:25617135

  9. Chronic cladribine administration increases amyloid beta peptide generation and plaque burden in mice.

    Directory of Open Access Journals (Sweden)

    Crystal D Hayes

    Full Text Available BACKGROUND: The clinical uses of 2-chloro-2'-deoxyadenosine (2-CDA or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS. Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known. METHODOLOGY: Here we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm. CONCLUSIONS: Taken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2

  10. Butyrylcholinesterase is Associated with β-Amyloid Plaques in the Transgenic APPSWE/PSEN1dE9 Mouse Model of Alzheimer Disease

    OpenAIRE

    Darvesh, Sultan; Cash, Meghan K.; Reid, G. Andrew; Martin, Earl; Mitnitski, Arnold; Geula, Changiz

    2012-01-01

    Histochemical analysis of Alzheimer disease (AD) brain tissues indicates that butyrylcholinesterase (BuChE) is present in β-amyloid (Aβ) plaques. The role of BuChE in AD pathology is unknown but an animal model developing similar BuChE-associated Aβ plaques could provide insights. The APPSWE/PSEN1dE9 mouse (ADTg), which develops Aβ plaques, was examined to determine if BuChE associates with these plaques, as in AD. We found that in mature ADTg mice, BuChE activity associated with Aβ plaques. ...

  11. A Novel liposomal nanoparticle for the imaging of amyloid plaque by MRI

    OpenAIRE

    Tanifum, Eric A; Ghaghada, Ketan; Vollert, Craig; Head, Elizabeth; Eriksen, Jason L.; Annapragada, Ananth

    2016-01-01

    Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo. The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy....

  12. Organotypic vibrosections from whole brain adult Alzheimer mice (overexpressing amyloid-precursor-protein with the Swedish-Dutch-Iowa mutations as a model to study clearance of beta-amyloid plaques

    Directory of Open Access Journals (Sweden)

    Christian eHumpel

    2015-04-01

    Full Text Available Alzheimer´s disease is a severe neurodegenerative disorder of the brain, pathologically characterized by extracellular beta-amyloid plaques, intraneuronal Tau inclusions, inflammation, reactive glial cells, vascular pathology and neuronal cell death. The degradation and clearance of beta-amyloid plaques is an interesting therapeutic approach, and the proteases neprilysin (NEP, insulysin and matrix metalloproteinases (MMP are of particular interest. The aim of this project was to establish and characterize a simple in vitro model to study the degrading effects of these proteases. Organoytpic brain vibrosections (120 µm thick were sectioned from adult (9 month old wildtype and transgenic mice (expressing amyloid precursor protein (APP harboring the Swedish K670N/M671L, Dutch E693Q, and Iowa D694N mutations; APP_SDI and cultured for 2 weeks. Plaques were stained by immunohistochemistry for beta-amyloid and Thioflavin S. Our data show that plaques were evident in 2 week old cultures from 9 month old transgenic mice. These plaques were surrounded by reactive GFAP+ astroglia and Iba1+ microglia. Incubation of fresh slices for 2 weeks with 1-0.1-0.01 µg/ml of NEP, insulysin, MMP-2 or MMP-9 showed that NEP, insulysin and MMP-9 markedly degradeded beta-amyloid plaques but only at the highest concentration. Our data provide for the first time a potent and powerful living brain vibrosection model containing a high number of plaques, which allows to rapidly and simply study the degradation and clearance of beta-amyloid plaques in vitro.

  13. Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.

    Science.gov (United States)

    Sadleir, Katherine R; Kandalepas, Patty C; Buggia-Prévot, Virginie; Nicholson, Daniel A; Thinakaran, Gopal; Vassar, Robert

    2016-08-01

    Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of

  14. A liposome-based therapeutic vaccine against β-amyloid plaques on the pancreas of transgenic NORBA mice

    OpenAIRE

    Nicolau, Claude; Greferath, Ruth; Balaban, Teodor Silviu; Lazarte, Jaime E.; Hopkins, Robert J.

    2002-01-01

    Immune tolerance to β-amyloid (Aβ) was broken in NORBA transgenic mice presenting Aβ plaques on their pancreases. Vaccination of Black C57, BALB/c, and NORBA mice with the synthetic Aβ1–16 sequence modified by covalently attaching two palmitoyl residues at each end of the peptide, subsequently reconstituted in liposomes–Lipid A elicited titers of 1:5,000 of anti-Aβ1–16 antibodies within 10 weeks after the first inoculation. On direct interaction, sera with antibody titers of 1:5,000 solubiliz...

  15. Amyloid-PET predicts inhibition of de novo plaque formation upon chronic γ-secretase modulator treatment.

    Science.gov (United States)

    Brendel, M; Jaworska, A; Herms, J; Trambauer, J; Rötzer, C; Gildehaus, F-J; Carlsen, J; Cumming, P; Bylund, J; Luebbers, T; Bartenstein, P; Steiner, H; Haass, C; Baumann, K; Rominger, A

    2015-10-01

    In a positron-emission tomography (PET) study with the β-amyloid (Aβ) tracer [(18)F]-florbetaben, we previously showed that Aβ deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. γ-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Aβ42 species without blocking general γ-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Aβ-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Aβ-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Aβ were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Δ%-SUVR, indicating individual response prediction. Insoluble Aβ42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Aβ-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover

  16. Neurogenic Responses to Amyloid-Beta Plaques in the Brain of Alzheimer's Disease-Like Transgenic (pPDGF-APPSw,Ind) Mice

    OpenAIRE

    Gan, Li; Qiao, Shuhong; Lan, Xun; Chi, Liying; Luo, Chun; Lien, Lindsey; Liu, Qing Yan; Liu, Rugao

    2007-01-01

    Formation and accumulation of amyloid-beta (Aβ) plaques are associated with declined memory and other neurocognitive function in Alzheimer's Disease (AD) patients. However, the effects of Aβ plaques on neural progenitor cells (NPCs) and neurogenesis from NPCs remain largely unknown. The existing data on neurogenesis in AD patients and AD-like animal models remain controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ (pNes-LacZ) reporter transgenic mice ...

  17. Three-dimensional reconstruction and analysis of structure characteristics on senile plaques of Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    YE Wei; LIU Jianwu; ZHOU Jiangning; HU Xiangyou; TANG Xiaowei

    2005-01-01

    Alzheimer's disease is a progressive neuro- degenerative disorder characterized by the presence of senile plaques primarily composed of amyloid ( in brain. Abnormal secretion and aggregation of amyloid ( are the key events in pathogenesis of Alzheimer's disease. Reduction of amyloid ( production and inhibition of amyloid ( aggregation to form senile plaques are hopeful strategies for the treatment and prevention of Alzheimer's disease. In the present study, the silver and immunohistochemical staining methods were applied to discover senile plaques in the hippocampus of Alzheimer's disease patients, and then images were processed and three-dimensionally reconstructed by Matlab and AVS software. The structure characteristics of senile plaques were measured through correlation function calculation and fractal dimension by a computer-aided method. Diffuse plaque had no amyloid center, but classic plaque presented compact central core structure; two types of plaques were both of porous structure, but the sizes of their pores were significantly different. Furthermore, there was difference in fractal dimension value between the diffuse plaque and classic plaque in the two staining methods. The comparison of structure characteristics between two types of plaques indicated that they developed independently. Establishment of the methods for reconstructing the three-dimen- sional structure of senile plaque and analyzing their structure characteristics is helpful for further study on the aggregation mechanism of senile plaque.

  18. Radioiodinated benzimidazole derivatives as single photon emission computed tomography probes for imaging of {beta}-amyloid plaques in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Cui Mengchao [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Ono, Masahiro, E-mail: ono@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kimura, Hiroyuki; Kawashima, Hidekazu [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Liu Boli [Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875 (China); Saji, Hideo, E-mail: hsaji@pharm.kyoto-u.ac.j [Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2011-04-15

    Five iodinated 2-phenyl-1H-benzo[d]imidazole derivatives were synthesized and evaluated as potential probes for {beta}-amyloid (A{beta}) plaques. One of the compounds, 4-(6-iodo-1H-benzo[d]imidazol-2-yl)-N,N-dimethylaniline (12), showed excellent affinity for A{beta}{sub 1-42} aggregates (K{sub i}=9.8 nM). Autoradiography with sections of postmortem Alzheimer's disease (AD) brain revealed that a radioiodinated probe [{sup 125}I]12, labeled A{beta} plaques selectively with low nonspecific binding. Biodistribution experiments with normal mice injected intravenously with [{sup 125}I]12 showed high uptake [4.14 percent injected dose per gram (% ID/g) at 2 min] into and rapid clearance (0.15% ID/g at 60 min) from the brain, which may bring about a good signal-to-noise ratio and therefore achieve highly sensitive detection of A{beta} plaques. In addition, [{sup 125}I]12 labeled amyloid plaques in vivo in an AD transgenic model. The preliminary results strongly suggest that [{sup 125}I]12 bears characteristics suitable for detecting amyloid plaques in vivo. When labeled with {sup 123}I, it may be a useful SPECT imaging agent for A{beta} plaques in the brain of living AD patients.

  19. Using bacterial inclusion bodies to screen for amyloid aggregation inhibitors

    OpenAIRE

    Villar-Piqué Anna; Espargaró Alba; Sabaté Raimon; de Groot Natalia S; Ventura Salvador

    2012-01-01

    Abstract Background The amyloid-β peptide (Aβ42) is the main component of the inter-neuronal amyloid plaques characteristic of Alzheimer's disease (AD). The mechanism by which Aβ42 and other amyloid peptides assemble into insoluble neurotoxic deposits is still not completely understood and multiple factors have been reported to trigger their formation. In particular, the presence of endogenous metal ions has been linked to the pathogenesis of AD and other neurodegenerative disorders. Results ...

  20. Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

    OpenAIRE

    Qing, Hong; He, Guiqiong; Ly, Philip T. T.; Fox, Christopher J; Staufenbiel, Matthias; Cai, Fang; Zhang, Zhuohua; Wei, Shengcai; Sun, Xiulian; Chen, Chia-Hsiung; Zhou, Weihui; Wang, Ke; Song, Weihong

    2008-01-01

    Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epileps...

  1. Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques

    Directory of Open Access Journals (Sweden)

    Virginia Garcia-Marin

    2009-11-01

    Full Text Available One of the main pathological hallmarks of Alzheimer’s disease (AD is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic and perisomatic (mostly GABAergic regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

  2. The Alzheimer Structural Connectome: Changes in Cortical Network Topology with Increased Amyloid Plaque Burden

    OpenAIRE

    Prescott, Jeffrey W.; Guidon, Arnaud; Doraiswamy, P. Murali; Roy Choudhury, Kingshuk; Liu, Chunlei; Petrella, Jeffrey R.

    2014-01-01

    Our cross-sectional study of baseline data from a national cohort of patients with Alzheimer disease, mild cognitive impairment, or normal cognition shows that increased cortical amyloid deposition is significantly associated with alterations in the topology of the structural connectome.

  3. Synthesis and evaluation of {sup 18}F-fluoroethylated benzothiazole derivatives for in vivo imaging of amyloid plaques in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Neumaier, B. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Max Planck Institute for Neurological Research, Klaus-Joachim-Zuelch Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Cologne (Germany)], E-mail: bernd.neumaier@nf.mpg.de; Deisenhofer, S. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Sommer, C. [Department of Neuropathology, University of Mainz (Germany); Solbach, C.; Reske, S.N. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Mottaghy, F. [Department of Nuclear Medicine, University of Ulm, Ulm (Germany); Department of Nuclear Medicine, RWTH Aachen, Aachen (Germany)

    2010-06-15

    Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [{sup 11}C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of {sup 11}C, longer lived {sup 18}F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [{sup 18}F]fluoroethoxy-substituted benzothiazole derivatives ([{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [{sup 18}F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [{sup 18}F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [{sup 18}F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [{sup 18}F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [{sup 18}F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.

  4. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology

    Directory of Open Access Journals (Sweden)

    Ferretti Maria

    2012-04-01

    Full Text Available Abstract Background A growing body of evidence indicates that inflammation is one of the earliest neuropathological events in Alzheimer's disease. Accordingly, we have recently shown the occurrence of an early, pro-inflammatory reaction in the hippocampus of young, three-month-old transgenic McGill-Thy1-APP mice in the absence of amyloid plaques but associated with intracellular accumulation of amyloid beta petide oligomers. The role of such a pro-inflammatory process in the progression of the pathology remained to be elucidated. Methods and results To clarify this we administered minocycline, a tetracyclic derivative with anti-inflammatory and neuroprotective properties, to young, pre-plaque McGill-Thy1-APP mice for one month. The treatment ended at the age of three months, when the mice were still devoid of plaques. Minocycline treatment corrected the up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 observed in young transgenic placebo mice. Furthermore, the down-regulation of inflammatory markers correlated with a reduction in amyloid precursor protein levels and amyloid precursor protein-related products. Beta-site amyloid precursor protein cleaving enzyme 1 activity and levels were found to be up-regulated in transgenic placebo mice, while minocycline treatment restored these levels to normality. The anti-inflammatory and beta-secretase 1 effects could be partly explained by the inhibition of the nuclear factor kappa B pathway. Conclusions Our study suggests that the pharmacological modulation of neuroinflammation might represent a promising approach for preventing or delaying the development of Alzheimer's disease neuropathology at its initial, pre-clinical stages. The results open new vistas to the interplay between inflammation and amyloid pathology.

  5. Plaque hemorrhage in carotid artery disease: Pathogenesis, clinical and biomechanical considerations

    OpenAIRE

    Teng, Zhongzhao; Sadat, Umar; Brown, Adam J.; Gillard, Jonathan H.

    2014-01-01

    Stroke remains the most prevalent disabling illness today, with internal carotid artery luminal stenosis due to atheroma formation responsible for the majority of ischemic cerebrovascular events. Severity of luminal stenosis continues to dictate both patient risk stratification and the likelihood of surgical intervention. But there is growing evidence to suggest that plaque morphology may help improve pre-existing risk stratification criteria. Plaque components such a fibrous tissue, lipid ri...

  6. Striking reduction of amyloid plaque burden in an Alzheimer's mouse model after chronic administration of carmustine

    OpenAIRE

    Hayes, Crystal D.; Dey, Debleena; Palavicini, Juan Pablo; Wang, Hongjie; Patkar, Kshitij A; Minond, Dimitriy; Nefzi, Adel; Lakshmana, Madepalli K.

    2013-01-01

    Background Currently available therapies for Alzheimer's disease (AD) do not treat the underlying cause of AD. Anecdotal observations in nursing homes from multiple studies strongly suggest an inverse relationship between cancer and AD. Therefore, we reasoned that oncology drugs may be effective against AD. Methods We screened a library of all the FDA-approved oncology drugs and identified bis-chloroethylnitrosourea (BCNU or carmustine) as an effective amyloid beta (Aβ) reducing compound. To ...

  7. Effective screen for amyloid β aggregation inhibitor using amyloid β-conjugated gold nanoparticles

    OpenAIRE

    Han, Sun-Ho; Chang, Yu Jin; Jung, Eun Sun; Kim, Jong-Won; Na, Duk Lyul; Mook-Jung, Inhee

    2010-01-01

    The abnormal aggregation of amyloid β (Aβ) and its subsequent intra- and extracellular accumulation constitute the disease-causing cascade of Alzheimer’s disease (AD). The detection of Aβ aggregates and senile plaque formation, however, is nearly impossible during early pathogenesis, and the absence of a convenient screen to validate the activity of Aβ aggregation regulators impedes the development of promising drug targets and diagnostic biomarkers for AD. Here, we conjugated amyloid β42 (Aβ...

  8. Green-fluorescent protein+ Astrocytes Attach to beta-Amyloid Plaques in an Alzheimer Mouse Model and GFPare Sensitive for Clasmatodendrosis

    Directory of Open Access Journals (Sweden)

    Christian eHumpel

    2016-04-01

    Full Text Available Alzheimer’s disease (AD is pathologically characterized by beta-amyloid (Aβ plaques and Tau pathology. It is well-established that Aβ plaques are surrounded by reactive astrocytes, highly expressing glial fibrillary acidic protein (GFAP. In order to study the cellular interaction of reactive astrocytes with Aβ plaques, we crossbred mice overexpressing amyloid precursor protein (APP with the Swedish-Dutch-Iowa mutations (APP-SweDI with mice expressing green fluorescent protein (GFP under the GFAP-promotor. Three-dimensional confocal microscopy revealed a tight association and intense sprouting of astrocytic fine branched processes towards Aβ plaques in 12 month old mice. In order to study phagocytosis, 110 µm thick brain slices from 12 month old crossbred mice were cultured overnight, however, we found that the GFP fluorescence faded away, distal processes degenerated and a complete loss of astrocytic morphology was seen (clasmatodendrosis. In summary, our data show that GFP+ reactive astrocytes make intense contact with Aβ plaques but these cells are highly vulnerable for degeneration.

  9. The detection of β-amyloid plaques in an Alzheimer's disease rat model with DDNP-SPIO

    International Nuclear Information System (INIS)

    Aim: To detect the β-amyloid plaques (Aβ) in a rat model of Alzheimer's disease (AD) using superparamagnetic iron oxide nanoparticles coated with 1,1-dicyano-2-[6-(dimethylamino)-naphthalene-2-yl] propene carboxyl derivative (DDNP-SPIO). Materials and methods: DDNP-SPIO was prepared in a previous trial. The binding affinity of DDNP-SPIO to Aβ was tested using fluorescence spectrophotometry in vitro. In vivo, five AD rats and five non-AD rats were intravenously injected with DDNP-SPIO at a dose of 76 μmol Fe/kg. Coronal T2*-weighted images were collected at baseline and repeated at 10, 30, and 60 min post-injection. Enhancement features of the two groups were analysed. After imaging, brain specimens were resected for Congo red and Prussian blue staining to assess the binding of DDNP-SPIO to Aβ deposits. Results: In vitro experiments indicated that the DDNP-SPIO nanoparticles displayed high binding affinities towards Aβ with a Kd value of 29.4 nmol/l. A significant decrease in SI was detected in the hippocampal area of AD rats after intravenous injection of the nanoparticles, but not in non-AD rats. The measurement of the percentage signal loss decreased to 52% in AD rats. In non-AD rats, only 10% signal loss was observed. There was a significant difference between the two groups (t = 4.533, p < 0.05). The signal decrease resulted from the binding of the DDNP-SPIO nanoparticles to the Aβ plaques, which was identified with Congo red and Prussian blue staining. Conclusion: The DDNP-SPIO nanoparticles could potentially be used for visualizing Aβ plaques, which may be helpful for diagnosing the early stages of AD and monitoring the effects of drug therapy. - Highlights: • A new targeted nanoparticle (DDNP-SPIO) for MRI detection of Aβ was synthesized • The DDNP-SPIO nanoparticles has the ability to detect the Aβ deposites in AD rats • The DDNP-SPIO nanoparticles could potentially be used for visualizing Aβ plaques, which may be helpful for

  10. Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC.

    Directory of Open Access Journals (Sweden)

    Sarah Vascellari

    Full Text Available Different transmissible spongiform encephalopathy (TSE-associated forms of prion protein (e.g. PrP(Sc can vary markedly in ultrastructure and biochemical characteristics, but each is propagated in the host. PrP(Sc propagation involves conversion from its normal isoform, PrP(C, by a seeded or templated polymerization mechanism. Such a mechanism is also the basis of the RT-QuIC and eQuIC prion assays which use recombinant PrP (rPrP(Sen as a substrate. These ultrasensitive detection assays have been developed for TSE prions of several host species and sample tissues, but not for murine models which are central to TSE pathogenesis research. Here we have adapted RT-QuIC and eQuIC to various murine prions and evaluated how seeding activity depends on glycophosphatidylinositol (GPI anchoring and the abundance of amyloid plaques and protease-resistant PrP(Sc (PrP(Res. Scrapie brain dilutions up to 10(-8 and 10(-13 were detected by RT-QuIC and eQuIC, respectively. Comparisons of scrapie-affected wild-type mice and transgenic mice expressing GPI anchorless PrP showed that, although similar concentrations of seeding activity accumulated in brain, the heavily amyloid-laden anchorless mouse tissue seeded more rapid reactions. Next we compared seeding activities in the brains of mice with similar infectivity titers, but widely divergent PrP(Res levels. For this purpose we compared the 263K and 139A scrapie strains in transgenic mice expressing P101L PrP(C. Although the brains of 263K-affected mice had little immunoblot-detectable PrP(Res, RT-QuIC indicated that seeding activity was comparable to that associated with a high-PrP(Res strain, 139A. Thus, in this comparison, RT-QuIC seeding activity correlated more closely with infectivity than with PrP(Res levels. We also found that eQuIC, which incorporates a PrP(Sc immunoprecipitation step, detected seeding activity in plasma from wild-type and anchorless PrP transgenic mice inoculated with 22L, 79A and/or RML

  11. Plaque deposition dependent decrease in 5-HT2A serotonin receptor in AbetaPPswe/PS1dE9 amyloid overexpressing mice

    DEFF Research Database (Denmark)

    Holm, Peter; Ettrup, Anders; Klein, Anders B;

    2010-01-01

    -HT2A receptor regulation in double transgenic AbetaPPswe/PS1dE9 mice which display excess production of Abeta and age-dependent increase in amyloid plaques. Three different age-groups, 4-month-old, 8- month-old, and 11-month-old were included in the study. [3H]-MDL100907, [3H]-escitalopram, and [11C...

  12. PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD), the most common age-related neuro-degenerative disorder, is characterized by the accumulation of amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thio-flavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice. (authors)

  13. Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.

    Directory of Open Access Journals (Sweden)

    Jin Chu

    Full Text Available The 5-lipoxygenase (5LO enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD, and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3 × Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.

  14. Bacterial Amyloid and DNA are Important Constituents of Senile Plaques: Further Evidence of the Spirochetal and Biofilm Nature of Senile Plaques

    Science.gov (United States)

    Miklossy, Judith

    2016-01-01

    It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer’s disease (AD) are made up by spirochetes. Spirochetes, are able to form biofilm in vitro. Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA, including spirochete-specific DNA, are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These results validate validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial and host derived Aβ are both constituents of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms result in a higher resistance to treatments and a more severe dementia. PMID:27314530

  15. Brain imaging with a novel β-amyloid plaque probe 131I-IMPY in Alzheimer's disease

    International Nuclear Information System (INIS)

    .6772, all P<0.05). Conclusion: 131I-IMPY as a β-amyloid plaque probe for brain SPECT imaging may be potentially helpful for early diagnosis of AD. (authors)

  16. Accumulation of amyloid-like Aβ1–42 in AEL (autophagy–endosomal–lysosomal vesicles: potential implications for plaque biogenesis

    Directory of Open Access Journals (Sweden)

    Daijun Ling

    2014-03-01

    Full Text Available Abnormal accumulation of Aβ (amyloid β within AEL (autophagy–endosomal–lysosomal vesicles is a prominent neuropathological feature of AD (Alzheimer's disease, but the mechanism of accumulation within vesicles is not clear. We express secretory forms of human Aβ1–40 or Aβ1–42 in Drosophila neurons and observe preferential localization of Aβ1–42 within AEL vesicles. In young animals, Aβ1–42 appears to associate with plasma membrane, whereas Aβ1–40 does not, suggesting that recycling endocytosis may underlie its routing to AEL vesicles. Aβ1–40, in contrast, appears to partially localize in extracellular spaces in whole brain and is preferentially secreted by cultured neurons. As animals become older, AEL vesicles become dysfunctional, enlarge and their turnover appears delayed. Genetic inhibition of AEL function results in decreased Aβ1–42 accumulation. In samples from older animals, Aβ1–42 is broadly distributed within neurons, but only the Aβ1–42 within dysfunctional AEL vesicles appears to be in an amyloid-like state. Moreover, the Aβ1–42-containing AEL vesicles share properties with AD-like extracellular plaques. They appear to be able to relocate to extracellular spaces either as a consequence of age-dependent neurodegeneration or a non-neurodegenerative separation from host neurons by plasma membrane infolding. We propose that dysfunctional AEL vesicles may thus be the source of amyloid-like plaque accumulation in Aβ1–42-expressing Drosophila with potential relevance for AD.

  17. Infectious agents in coronary atheromas: a possible role in the pathogenesis of plaque rupture and acute myocardial infarction.

    Science.gov (United States)

    Higuchi, Maria de Lourdes; Ramires, Jose A F

    2002-01-01

    In this review we report our recent findings of histopathological features of plaque instability and the association with Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) infection, studying thrombosed coronary artery segments (CAS) of patients who died due to acute myocardial infarction. Vulnerable plaques are known to be associated with fat atheromas and inflammation of the plaque. Here we demonstrated that vulnerability is also related with focal positive vessel remodeling that maintains relatively well preserved lumen even in the presence of large atheromatous plaques. This phenomena may explain why the cinecoronariography may not detect large and dangerous vulnerable plaques. Greater amount of these bacteria in vulnerable plaques is associated with adventitial inflammation and positive vessel remodeling: the mean numbers of lymphocytes were significantly higher in adventitia than in the plaque, good direct correlation was obtained between numbers of CD20 B cells and numbers of CP infected cells in adventitia, and between % area of MP-DNA in the plaque and cross sectional area of the vessel, suggesting a cause-effect relationship. Mycoplasma is a bacterium that needs cholesterol for proliferation and may increase virulence of other infectious agents. In conclusion, co-infection by Mycoplasma pneumoniae and Chlamydia pneumoniae may represent an important co-factor for plaque instability, leading to coronary plaque thrombosis and acute myocardial infarction, since larger amount of these bacteria strongly correlated with histological signs of more vulnerability of the plaque. The search of CMV and Helicobacter pilori in these tissues resulted negative. PMID:12219114

  18. Infectious agents in coronary atheromas: a possible role in the pathogenesis of plaque rupture and acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    HIGUCHI Maria de Lourdes

    2002-01-01

    Full Text Available In this review we report our recent findings of histopathological features of plaque instability and the association with Mycoplasma pneumoniae (MP and Chlamydia pneumoniae (CP infection, studying thrombosed coronary artery segments (CAS of patients who died due to acute myocardial infarction. Vulnerable plaques are known to be associated with fat atheromas and inflammation of the plaque. Here we demonstrated that vulnerability is also related with focal positive vessel remodeling that maintains relatively well preserved lumen even in the presence of large atheromatous plaques. This phenomena may explain why the cinecoronariography may not detect large and dangerous vulnerable plaques. Greater amount of these bacteria in vulnerable plaques is associated with adventitial inflammation and positive vessel remodeling: the mean numbers of lymphocytes were significantly higher in adventitia than in the plaque, good direct correlation was obtained between numbers of CD20 B cells and numbers of CP infected cells in adventitia, and between % area of MP-DNA in the plaque and cross sectional area of the vessel, suggesting a cause-effect relationship. Mycoplasma is a bacterium that needs cholesterol for proliferation and may increase virulence of other infectious agents. In conclusion, co-infection by Mycoplasma pneumoniae and Chlamydia pneumoniae may represent an important co-factor for plaque instability, leading to coronary plaque thrombosis and acute myocardial infarction, since larger amount of these bacteria strongly correlated with histological signs of more vulnerability of the plaque. The search of CMV and Helicobacter pilori in these tissues resulted negative.

  19. Infectious agents in coronary atheromas: a possible role in the pathogenesis of plaque rupture and acute myocardial infarction

    OpenAIRE

    Maria de Lourdes HIGUCHI; Jose A. F. RAMIRES

    2002-01-01

    In this review we report our recent findings of histopathological features of plaque instability and the association with Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) infection, studying thrombosed coronary artery segments (CAS) of patients who died due to acute myocardial infarction. Vulnerable plaques are known to be associated with fat atheromas and inflammation of the plaque. Here we demonstrated that vulnerability is also related with focal positive vessel remodeling that mai...

  20. Serum amyloid A: An acute-phase protein involved in tumour pathogenesis

    Science.gov (United States)

    Sodin-Semrl, S.; Kovacevic, A.

    2016-01-01

    The synthesis of acute-phase protein serum amyloid A (SAA) is largely regulated by inflammation-associated cytokines and a high concentration of circulating SAA may represent an ideal marker for acute and chronic inflammatory diseases. However, SAA is also synthesized in extrahepatic tissues, e.g. human carcinoma metastases and cancer cell lines. An increasing body of in vitro data supports the concept of involvement of SAA in carcinogenesis and neoplastic diseases. Accumulating evidence suggests that SAA might be included in a group of biomarkers to detect a pattern of physiological events that reflect the growth of malignancy and host response. This review is meant to provide a broad overview of the many ways that SAA could contribute to tumour development, and accelerate tumour progression and metastasis, and to gain a better understanding of this acute-phase reactant as a possible link between chronic inflammation and neoplasia. PMID:18726069

  1. GMP-compliant automated synthesis of [18F]AV-45 (Florbetapir F 18) for imaging β-amyloid plaques in human brain

    International Nuclear Information System (INIS)

    We report herein the Good Manufacturing Practice (GMP)-compliant automated synthesis of 18F-labeled styrylpyridine, AV-45 (Florbetapir), a novel tracer for positron emission tomography (PET) imaging of β-amyloid (Aβ) plaques in the brain of Alzheimer's disease patients. [18F]AV-45 was prepared in 105 min using a tosylate precursor with Sumitomo modules for radiosynthesis under GMP-compliant conditions. The overall yield was 25.4±7.7% with a final radiochemical purity of 95.3±2.2% (n=19). The specific activity of [18F]AV-45 reached as high as 470±135 TBq/mmol (n=19). The present studies show that [18F]AV-45 can be manufactured under GMP-compliant conditions and could be widely available for routine clinical use.

  2. Selenomethionine reduces the deposition of beta-amyloid plaques by modulating β-secretase and enhancing selenoenzymatic activity in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zhang, Zhong-Hao; Chen, Chen; Wu, Qiu-Yan; Zheng, Rui; Liu, Qiong; Ni, Jia-Zuan; Hoffmann, Peter R; Song, Guo-Li

    2016-08-01

    Alzheimer's disease (AD) is characterized by the production of large amounts of beta-amyloid (Aβ) and the accumulation of extracellular senile plaques, which have been considered to be potential targets in the treatment of AD. Selenium (Se) is a nutritionally essential trace element with known antioxidant potential and Se status has been shown to decrease with age and has a close relationship with cognitive competence in AD. Selenomethionine (Se-Met), a major reserve form of Se in organisms, has been shown in our previous study to ameliorate the decline in cognitive function, increase oxidation resistance, and reduce tau hyperphosphorylation in a triple transgenic mouse model of AD. However, it has not been reported whether Se-Met has any effects on Aβ pathology in AD mice. To study the effect of Se-Met on Aβ pathology and the function of selenoproteins/selenoenzymes in 3× Tg-AD mice, 3× Tg-AD mice at 8 months of age were treated with Se-Met for 3 months. Se-Met led to significantly reduced production and deposition of Aβ, down-regulation of β-secretase levels and enhanced activity of selenoenzymes as well as increased levels of Se in the hippocampus and cortex. Se-Met reduces amyloidogenic processing of amyloid precursor protein while modulating β-secretase and selenoenzymatic activity in AD mice. These results indicate that Se-Met might exert its therapeutic effect through multiple pathways in AD. PMID:27465436

  3. A new molecular model for Congo Red-β amyloid interaction: implications for diagnosis and inhibition of brain plaque formation in Alzheimer's disease

    Science.gov (United States)

    Zhang, Kristine A.; Li, Yat

    2015-08-01

    Alzheimer's disease (AD), an age-related neurodegenerative disorder, is the seventh leading cause of death in the United States. One strong pathological indicator of AD is senile plaques, which are aggregates of fibrils formed from amyloid β (Aβ) peptides. Thus, detection and inhibition of Aβ aggregation are critical for the prevention and treatment of AD. Congo red (CR) is one of the most widely used dye molecules for probing as well as inhabiting Aβ aggregation. However, the nature of interaction between CR and Aβ is not well understood. In this research, we systematically studied the interaction between CR and Aβ using a combination of optical techniques, including electronic absorption, fluorescence, Raman scattering, and circular dichroism, to provide detailed information with molecular specificity and high sensitivity. Compared to CR alone, interaction of the dye with Aβ results in a new absorption peak near 540 nm and significantly enhanced photoluminescence as well as Raman signal. Our results led us to propose a new model suggesting that CR exists primarily in a micellar form, resembling H-aggregates, in water and dissociates into monomers upon interaction with Aβ. This model has significant implications for the development of new strategies to detect and inhibit brain plaques for treatment of neurological diseases like AD.

  4. The synthesis and evaluation of near-infrared probes with barbituric acid acceptors for in vivo detection of amyloid plaques.

    Science.gov (United States)

    Zhou, Kaixiang; Fu, Hualong; Feng, Liang; Cui, Mengchao; Dai, Jiapei; Liu, Boli

    2015-07-25

    A new array of near-infrared probes containing barbituric acid acceptors has been developed as Aβ imaging agents. These probes displayed long-emission wavelengths and large Stokes shifts, as well as high affinities for Aβ aggregates. In vivo and ex vivo studies demonstrated that BBTOM-3 could intensely label Aβ plaques in the brains of transgenic mice. PMID:26103205

  5. Amyloid beta peptide immunotherapy in Alzheimer disease.

    Science.gov (United States)

    Delrieu, J; Ousset, P J; Voisin, T; Vellas, B

    2014-12-01

    Recent advances in the understanding of Alzheimer's disease pathogenesis have led to the development of numerous compounds that might modify the disease process. Amyloid β peptide represents an important molecular target for intervention in Alzheimer's disease. The main purpose of this work is to review immunotherapy studies in relation to the Alzheimer's disease. Several types of amyloid β peptide immunotherapy for Alzheimer's disease are under investigation, active immunization and passive administration with monoclonal antibodies directed against amyloid β peptide. Although immunotherapy approaches resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not show significant cognitive effect for the moment. Currently, several amyloid β peptide immunotherapy approaches are under investigation but also against tau pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate that intervention appears to be more effective in early stages of amyloid accumulation in particular solanezumab with a potential impact at mild Alzheimer's disease, highlighting the importance of diagnosing Alzheimer's disease as early as possible and undertaking clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer's disease in the first place. So a new third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild Alzheimer's disease and evidence of amyloid burden has been started. Thus, currently, amyloid intervention is realized at early stage of the Alzheimer's disease in clinical trials, at prodromal Alzheimer's disease, or at asymptomatic subjects or at risk to develop Alzheimer's disease and or at asymptomatic subjects with autosomal dominant mutation. PMID:25459121

  6. Small-Animal PET Imaging of Amyloid-Beta Plaques with [11C]PiB and Its Multi-Modal Validation in an APP/PS1 Mouse Model of Alzheimer's Disease

    OpenAIRE

    Manook, André; Yousefi, Behrooz H.; Willuweit, Antje; Platzer, Stefan; Reder, Sybille; Voss, Andreas; Huisman, Marc; Settles, Markus; Neff, Frauke; Velden, Joachim; Schoor, Michael; von der Kammer, Heinz; Wester, Hans-Jürgen; Schwaiger, Markus; Henriksen, Gjermund

    2012-01-01

    In vivo imaging and quantification of amyloidplaque (Aβ) burden in small-animal models of Alzheimer's disease (AD) is a valuable tool for translational research such as developing specific imaging markers and monitoring new therapy approaches. Methodological constraints such as image resolution of positron emission tomography (PET) and lack of suitable AD models have limited the feasibility of PET in mice. In this study, we evaluated a feasible protocol for PET imaging of Aβ in mouse brain...

  7. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Vieitez, Elena; Ni, Ruiqing; Voytenko, Larysa; Marutle, Amelia [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nanyang Technological University, NTU - Imperial College, Lee Kong Chian School of Medicine, Singapore (Singapore); Toth, Miklos; Haeggkvist, Jenny [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2015-04-17

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer {sup 11}C-AZD2184 and the astroglial tracer {sup 11}C-deuterium-L-deprenyl ({sup 11}C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using {sup 3}H-AZD2184, {sup 3}H-Pittsburgh compound B (PIB) and {sup 3}H-L-deprenyl and immunostaining performed with antibodies for Aβ{sub 42} and glial fibrillary acidic protein (GFAP) in sagittal brain sections. {sup 11}C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal {sup 11}C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography {sup 3}H-AZD2184 and {sup 3}H-PIB binding confirmed the in vivo findings with {sup 11}C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in {sup 3}H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ{sub 42} deposits in the cortex and hippocampus and more

  8. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    International Nuclear Information System (INIS)

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer 11C-AZD2184 and the astroglial tracer 11C-deuterium-L-deprenyl (11C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using 3H-AZD2184, 3H-Pittsburgh compound B (PIB) and 3H-L-deprenyl and immunostaining performed with antibodies for Aβ42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections. 11C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal 11C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography 3H-AZD2184 and 3H-PIB binding confirmed the in vivo findings with 11C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in 3H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ42 deposits in the cortex and hippocampus and more GFAP+ reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe

  9. Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex.

    Science.gov (United States)

    Ashby, Emma L; Miners, James S; Kehoe, Patrick G; Love, Seth

    2016-01-01

    Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n = 20) relative to normotensive cases (n = 62) and was also significantly higher in treated (n = 9) than untreated hypertensives (n = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n = 21) than normotensive cases (n = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n = 9) than untreated hypertensives (n = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism. PMID:26836178

  10. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism

    Directory of Open Access Journals (Sweden)

    Anckarsäter Henrik

    2010-06-01

    Full Text Available Abstract Background The metabolism of amyloid precursor protein (APP and β-amyloid (Aβ is widely studied in Alzheimer's disease, where Aβ deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB. Methods The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy and 22 healthy controls. CSF was analysed for the β-amyloid peptides Aβ38, Aβ40 and Aβ42, and the amyloid precursor protein (APP isoforms α-sAPP and β-sAPP. CSF total-tau (T-tau, phosphorylated tau (P-tau and neurofilament protein (NFL were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. Results In the cross-sectional study, LNB patients had lower levels of CSF α-sAPP, β-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF α-sAPP, β-sAPP and P-tau at baseline, which all increased towards normal at follow-up. Conclusions Amyloid metabolism is altered in LNB. CSF levels of α-sAPP, β-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

  11. Highly Sensitive Near-Infrared Fluorophores for in Vivo Detection of AmyloidPlaques in Alzheimer's Disease.

    Science.gov (United States)

    Fu, Hualong; Cui, Mengchao; Zhao, Liu; Tu, Peiyu; Zhou, Kaixiang; Dai, Jiapei; Liu, Boli

    2015-09-10

    Alzheimer's disease (AD) is pathologically characterized by the accumulation of β-amyloid (Aβ) deposits in the parenchymal and cortical brain. In this work, we designed, synthesized, and evaluated a series of near-infrared (NIR) probes with electron donor-acceptor end groups interacting through a π-conjugated system for the detection of Aβ deposits in the brain. Among these probes, 3b and 3c had excellent fluorescent properties (emission maxima > 650 nm and high quantum yields) and displayed high sensitivity and high affinities to Aβ aggregates (3b, Kd = 8.8 nM; 3c, Kd = 1.9 nM). Both 3b and 3c could readily penetrate the blood-brain barrier with high initial brain uptake and fast to moderate washout from the brain. In vivo NIR imaging revealed that 3b and 3c could efficiently differentiate transgenic and wild-type mice. In summary, our research provides new hints for developing smarter and more activatable NIR probes targeting Aβ. PMID:26262759

  12. CXCL8 protects human neurons from amyloid-β-induced neurotoxicity: Relevance to Alzheimer’s disease

    OpenAIRE

    Ashutosh; KOU, WEI; Cotter, Robin; Borgmann, Kathleen; Li WU; Persidsky, Raisa; Sakhuja, Namita; GHORPADE, ANUJA

    2011-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid-β (Aβ) deposition in senile plaques colocalized with activated microglia and astrocytes. Recent studies suggest that CXCL8 is involved in the AD pathogenesis. The objective of this study was to determine the cellular sources of CXCL8 in the central nervous system during AD pathogenesis, and investigate the effects of CXCL8 on neuronal survival and/or functions. Our results showed significantly higher CXCL8 levels...

  13. The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease

    OpenAIRE

    Portelius, Erik; Fortea, Juan; Molinuevo, Jose Luis; Gustavsson, Mikael K; Andreasson, Ulf; Sanchez-Valle, Raquel

    2012-01-01

    There are several familial forms of Alzheimer's disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP). In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-–2) and it is now widely accepted that Aβ is related to the pathogenesis of AD and that Aβ may both imp...

  14. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Science.gov (United States)

    Hansen, Henrik H; Fabricius, Katrine; Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer's disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E) and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  15. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1 Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Henrik H Hansen

    Full Text Available One of the major histopathological hallmarks of Alzheimer's disease (AD is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1 receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP and presenilin-1 (PS1 are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer's disease carrying different clinical APP/PS1 mutations, i.e. the 'London' (hAPPLon/PS1A246E and 'Swedish' mutation variant (hAPPSwe/PS1ΔE9 of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c., or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.. In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD.

  16. Long-Term Treatment with Liraglutide, a Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist, Has No Effect on β-Amyloid Plaque Load in Two Transgenic APP/PS1 Mouse Models of Alzheimer’s Disease

    Science.gov (United States)

    Barkholt, Pernille; Kongsbak-Wismann, Pernille; Schlumberger, Chantal; Jelsing, Jacob; Terwel, Dick; Termont, Annelies; Pyke, Charles; Knudsen, Lotte Bjerre; Vrang, Niels

    2016-01-01

    One of the major histopathological hallmarks of Alzheimer’s disease (AD) is cerebral deposits of extracellular β-amyloid peptides. Preclinical studies have pointed to glucagon-like peptide 1 (GLP-1) receptors as a potential novel target in the treatment of AD. GLP-1 receptor agonists, including exendin-4 and liraglutide, have been shown to promote plaque-lowering and mnemonic effects of in a number of experimental models of AD. Transgenic mouse models carrying genetic mutations of amyloid protein precursor (APP) and presenilin-1 (PS1) are commonly used to assess the pharmacodynamics of potential amyloidosis-lowering and pro-cognitive compounds. In this study, effects of long-term liraglutide treatment were therefore determined in two double APP/PS1 transgenic mouse models of Alzheimer’s disease carrying different clinical APP/PS1 mutations, i.e. the ‘London’ (hAPPLon/PS1A246E) and ‘Swedish’ mutation variant (hAPPSwe/PS1ΔE9) of APP, with co-expression of distinct PS1 variants. Liraglutide was administered in 5 month-old hAPPLon/PS1A246E mice for 3 months (100 or 500 ng/kg/day, s.c.), or 7 month-old hAPPSwe/PS1ΔE9 mice for 5 months (500 ng/kg/day, s.c.). In both models, regional plaque load was quantified throughout the brain using stereological methods. Vehicle-dosed hAPPSwe/PS1ΔE9 mice exhibited considerably higher cerebral plaque load than hAPPLon/PS1A246E control mice. Compared to vehicle-dosed transgenic controls, liraglutide treatment had no effect on the plaque levels in hAPPLon/PS1A246E and hAPPSwe/PS1ΔE9 mice. In conclusion, long-term liraglutide treatment exhibited no effect on cerebral plaque load in two transgenic mouse models of low- and high-grade amyloidosis, which suggests differential sensitivity to long-term liraglutide treatment in various transgenic mouse models mimicking distinct pathological hallmarks of AD. PMID:27421117

  17. Imaging β-amyloid fibrils in Alzheimer's disease: a critical analysis through simulation of amyloid fibril polymerization

    International Nuclear Information System (INIS)

    The polymerization of β-amyloid (Aβ) peptides into fibrillary plaques is implicated, in part, in the pathogenesis of Alzheimer's disease. Aβ molecular imaging probes (Aβ-MIPs) have been introduced in an effort to quantify amyloid burden or load, in subjects afflicted with AD by invoking the classic PET receptor model for the quantitation of neuronal receptor density. In this communication, we explore conceptual differences between imaging the density of amyloid fibril polymers and neuronal receptors. We formulate a mathematical model for the polymerization of Aβ with parameters that are mapped to biological modulators of fibrillogenesis and introduce a universal measure for amyloid load to accommodate various interactions of Aβ-MIPs with fibrils. Subsequently, we hypothesize four Aβ-MIPs and utilize the fibrillogenesis model to simulate PET tissue time activity curves (TACs). Given the unique nature of polymer growth and resulting PET TAC, the four probes report differing amyloid burdens for a given brain pathology, thus complicating the interpretation of PET images. In addition, we introduce the notion of an MIP's resolution, apparent maximal binding site concentration, optimal kinetic topology and its resolving power in characterizing the pathological progression of AD and the effectiveness of drug therapy. The concepts introduced in this work call for a new paradigm that goes beyond the classic parameters B max and K D to include binding characteristics to polymeric peptide aggregates such as amyloid fibrils, neurofibrillary tangles and prions

  18. Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation

    Czech Academy of Sciences Publication Activity Database

    Koistinaho, M.; Kettunen, M. I.; Goldsteins, G.; Keinänen, R.; Salminen, A.; Ort, Michael; Bureš, Jan; Liu, D.; Kauppinen, R. A.; Higgins, L. S.; Koistinaho, J.

    2002-01-01

    Roč. 99, č. 3 (2002), s. 1610-1615. ISSN 0027-8424 R&D Projects: GA ČR GA309/00/1656 Institutional research plan: CEZ:AV0Z5011922 Keywords : Beta-amyloid * Alzheimer disease * brain ischemia Subject RIV: FH - Neurology Impact factor: 10.701, year: 2002

  19. Synthesis and evaluation of a phenylbenzothiazole-based 99mTc(CO)3-radiotracer for possible application in imaging of β-amyloid plaques in Alzheimer's disease

    International Nuclear Information System (INIS)

    The 2-phenyl benzothiazole pharmacophore is known to have high affinity for amyloid beta (Aβ) and is therefore derivatized, to [N-(4'-benzothiazol-pyridin-2-yl-methyl-amino)-acetic acid (BTPAA)] for radiolabeling with [99mTc(CO)3(H2O)3]+ precursor. The radiotracer, 99mTc(CO)3-BTPAA is evaluated in vitro and in vivo to determine its binding with the Aβ and ability to cross the blood brain barrier. The radiotracer prepared in >95 % radiochemical yield, showed ∼25 % inhibition in presence of thioflavin-T, indicating its specificity towards aggregated Aβ protein. The radiotracer also showed brain uptake of 0.25 ± 0.04 % injected dose/g at 2 min post injection, indicating its ability to cross the blood brain barrier. (author)

  20. Expression of complement system components during aging and amyloid deposition in APP transgenic mice

    Directory of Open Access Journals (Sweden)

    Wiederhold Karl-Heinz

    2009-11-01

    Full Text Available Abstract Background A causal role of the complement system in Alzheimer's disease pathogenesis has been postulated based on the identification of different activated components up to the membrane attack complex at amyloid plaques in brain. However, histological studies of amyloid plaque bearing APP transgenic mice provided only evidence for an activation of the early parts of the complement cascade. To better understand the contribution of normal aging and amyloid deposition to the increase in complement activation we performed a detailed characterization of the expression of the major mouse complement components. Methods APP23 mice expressing human APP751 with the Swedish double mutation as well as C57BL/6 mice were used at different ages. mRNA was quantified by Realtime PCR and the age- as well as amyloid induced changes determined. The protein levels of complement C1q and C3 were analysed by Western blotting. Histology was done to test for amyloid plaque association and activation of the complement cascade. Results High mRNA levels were detected for C1q and some inhibitory complement components. The expression of most activating components starting at C3 was low. Expression of C1q, C3, C4, C5 and factor B mRNA increased with age in control C57BL/6 mice. C1q and C3 mRNA showed a substantial additional elevation during amyloid formation in APP23 mice. This increase was confirmed on the protein level using Western blotting, whereas immunohistology indicated a recruitment of complement to amyloid plaques up to the C3 convertase. Conclusion Early but not late components of the mouse complement system show an age-dependent increase in expression. The response to amyloid deposition is comparatively smaller. The low expression of C3 and C5 and failure to upregulate C5 and downstream components differs from human AD brain and likely contributes to the lack of full complement activation in APP transgenic mice.

  1. Synthetic peptide homologous to β protein from Alzheimer's disease forms amyloid-like fibrils in vitro

    International Nuclear Information System (INIS)

    Progressive amyloid deposition in senile plaques and cortical blood vessels may play a central role in the pathogenesis of Alzheimer's disease. The authors have used x-ray diffraction and electron microscopy to study the molecular organization and morphology of macromolecular assemblies formed by three synthetic peptides homologous to β protein of brain amyloid: β-(1-28), residues 1-28 of the β protein; [Ala1-β-(1-28), β-(1-28) with alanine substituted for lysine at position 16; and β-(18-28), residues 18-28 of the β protein. β-(1-28) readily formed fibrils in vitro that were similar in ultrastructure to the in vivo amyloid and aggregated into large bundles resembling those of senile plaque cores. X-ray patterns from partially dried, oriented pellets showed a cross-β-conformation. [Ala16]β-(1-28) formed β-pleated sheet assemblies that were dissimilar to in vivo fibrils. The width of the 10-A spacing indicated stacks of about six sheets. Thus, substitution of the uncharged alanine for the positively charged lysine in the β-strand region enhances the packing of the sheets and dramatically alters the type of macromolecular aggregate formed. Β-(18-28) formed assemblies that had even a greater number of stacked sheets. The findings on these homologous synthetic assemblies help to define the specific sequence that is required to form Alzheimer's-type amyloid fibrils, thus providing an in vitro model of age-related cerebral amyloidogenesis

  2. Micro-MRI study of cerebral aging: ex vivo detection of hippocampal sub-field reorganization, micro-hemorrhages and amyloid plaques in mouse lemur primates

    International Nuclear Information System (INIS)

    Mouse lemurs are non-human primate models of cerebral aging and neuro-degeneration. Much smaller than other primates, they recapitulate numerous features of human brain aging, including progressive cerebral atrophy and correlation between regional atrophy and cognitive impairments. Characterization of brain atrophy in mouse lemurs has been done by MRI measures of regional CSF volume and by MRI measures of regional atrophy. Here, we further characterize mouse lemur brain aging using ex vivo MR microscopy (31 μm in-plane resolution). First, we performed a non-biased, direct volumetric quantification of dentate gyrus and extended Ammon's horn. We show that both dentate gyrus and Ammon's horn undergo an age-related reorganization leading to a growth of the dentate gyrus and an atrophy of the Ammon's horn, even in the absence of global hippocampal atrophy. Second, on these first MR microscopic images of the mouse lemur brain, we depicted cortical and hippocampal hypointense spots. We demonstrated that their incidence increases with aging and that they correspond either to amyloid deposits or to cerebral micro-hemorrhages. (authors)

  3. Synthesis and evaluation of a phenylbenzothiazole-based 99mTc(CO)3-radiotracer for possible application in imaging β-amyloid plaque

    International Nuclear Information System (INIS)

    Radiopharmaceuticals targeting amyloid beta (Aβ) deposits in brain are useful in early diagnosis of Alzheimer's disease and monitoring the effectiveness of therapeutic treatments. Hence benzothiazole known to have high affinity for Aβ has been derivatized in order to introduce pyridine and amino acetic acid moiety for radiolabeling with (99mTc(CO)3(H2O)3)+ precursor. The radiotracer, 99mTc(CO)3-BTPAMA was tested for in vitro stability, serum stability and stability towards exchange with other ligands (histidine and cysteine). In vivo biodistribution studies to determine the pharmacokinetics and ability of the radiotracer to cross the blood brain barrier were carried out in normal Swiss mice. The radiotracer prepared in >95% radiochemical yield was found to be stable in vitro for 6 hours as well as in serum and in presence of other ligands as determined by HPLC. Biodistribution studies in normal Swiss mice showed brain uptake of 0.25±0.04% ID/g at 2 min p.i, indicating the ability of the radiotracer to cross the blood brain barrier. (author)

  4. Probing amyloid-β pathology in transgenic Alzheimer's disease (tgArcSwe) mice using MALDI imaging mass spectrometry.

    Science.gov (United States)

    Carlred, Louise; Michno, Wojciech; Kaya, Ibrahim; Sjövall, Peter; Syvänen, Stina; Hanrieder, Jörg

    2016-08-01

    The pathological mechanisms underlying Alzheimer's disease (AD) are still not understood. The disease pathology is characterized by the accumulation and aggregation of amyloid-β (Aβ) peptides into extracellular plaques, however the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used to study Aβ deposition in transgenic mouse brain tissue and to elucidate the plaque-associated chemical microenvironment. The imaging experiments were performed in brain sections of transgenic Alzheimer's disease mice carrying the Arctic and Swedish mutation of amyloid-beta precursor protein (tgArcSwe). Multivariate image analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their chemical identity. This include cortical and hippocampal Aβ deposits, whose amyloid peptide content was further verified using immunohistochemistry and laser microdissection followed by MALDI MS analysis. Subsequent statistical analysis on spectral data of regions of interest revealed brain region-specific differences in Aβ peptide aggregation. Moreover, other plaque-associated protein species were identified including macrophage migration inhibitory factor suggesting neuroinflammatory processes and glial cell reactivity to be involved in AD pathology. The presented data further highlight the potential of IMS as a powerful approach in neuropathology. Hanrieder et al. described an imaging mass spectrometry based study on comprehensive spatial profiling of C-terminally truncated Aβ species within individual plaques in tgArcSwe mice. Here, brain region-dependent differences in Aβ truncation and other plaque-associated proteins, such as

  5. FKBP12 regulates the localization and processing of amyloid precursor protein in human cell lines

    Indian Academy of Sciences (India)

    Fan-Lun Liu; Ting-Yi Liu; Fan-Lu Kung

    2014-03-01

    One of the pathological hallmarks of Alzheimer’s disease is the presence of insoluble extracellular amyloid plaques. These plaques are mainly constituted of amyloid beta peptide (A), a proteolytic product of amyloid precursor protein (APP). APP processing also generates the APP intracellular domain (AICD). We have previously demonstrated that AICD interacts with FKBP12, a peptidyl-prolyl cis-trans isomerase (PPIase) ubiquitous in nerve systems. This interaction was interfered by FK506, a clinically used immunosuppressant that has recently been reported to be neuroprotective. To elucidate the roles of FKBP12 in the pathogenesis of Alzheimer’s disease, the effect of FKBP12 overexpression on APP processing was evaluated. Our results revealed that APP processing was shifted towards the amyloidogenic pathway, accompanied by a change in the subcellular localization of APP, upon FKBP12 overexpression. This FKBP12-overexpression-induced effect was reverted by FK506. These findings support our hypothesis that FKBP12 may participate in the regulation of APP processing. FKBP12 overexpression may lead to the stabilization of a certain isomer (presumably the cis form) of the Thr668-Pro669 peptide bond in AICD, therefore change its affinity to flotillin-1 or other raft-associated proteins, and eventually change the localization pattern and cause a shift in the proteolytic processing of APP.

  6. Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

    Science.gov (United States)

    Liu, Yu-Hui; Wang, Ye-Ran; Xiang, Yang; Zhou, Hua-Dong; Giunta, Brian; Mañucat-Tan, Noralyn B; Tan, Jun; Zhou, Xin-Fu; Wang, Yan-Jiang

    2015-02-01

    Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies. PMID:24733588

  7. Biophysical insights into the membrane interaction of the core amyloid-forming Aβ40 fragment K16-K28 and its role in the pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Bera, Swapna; Korshavn, Kyle J; Kar, Rajiv K; Lim, Mi Hee; Ramamoorthy, Ayyalusamy; Bhunia, Anirban

    2016-06-22

    The aggregation of amyloid-β (Aβ) on neuronal membranes is implicated in both neuronal toxicity and the progression of Alzheimer's disease. Unfortunately, the heterogeneous environment that results from peptide aggregation in the presence of lipids makes the details of these pathways difficult to interrogate. In this study, we report an investigation of the membrane interaction of an Aβ fragment (K16LVFFAEDVGSNK28, KK13), which maintains the amyloidogenic nature of the full-length peptide and is implicated in membrane-mediated folding, through a combination of NMR spectroscopy and molecular dynamics simulations. Despite KK13's ability to form amyloids in solution, the monomer remains unstructured in the presence of lipid bilayers, unlike its full-length parent peptide. Additionally, NMR and molecular dynamics simulation results support that the presence of GM1 ganglioside, a lipid which strongly promotes binding between Aβ and lipid bilayers, promotes KK13 binding to but not folding on the membrane. Finally, we show that the peptide partitions between the membrane and aqueous solution based on the hydrophobicity of the N-terminal residues, regardless of lipid composition. These results support previous discoveries suggesting the importance of GM1 ganglioside in exacerbating membrane-driven aggregation while identifying the potential importance of C-terminal residues in membrane binding and folding, which has previously been unclear. PMID:27282693

  8. Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer’s disease

    OpenAIRE

    Wang, Chiou-Miin; deVries, Sarah; Camboni, Marybeth; Glass, Matthew; Martin, Paul T.

    2010-01-01

    Vaccination has become an important therapeutic approach to the treatment of Alzheimer’s disease (AD), however, immunization with Aβ amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Aβ1–40- and Aβ1–42-amyloid and blocks subsequent Aβ amyloid aggregation. Immunization of mice with SDPM1 induced peptide mimot...

  9. Prevalence of amyloid PET positivity in dementia syndromes

    DEFF Research Database (Denmark)

    Ossenkoppele, Rik; Jansen, Willemijn J; Rabinovici, Gil D;

    2015-01-01

    IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use...... individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION: Case reports and studies on....... The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status...

  10. Amyloid-beta Positron Emission Tomography Imaging Probes : A Critical Review

    NARCIS (Netherlands)

    Kepe, Vladimir; Moghbel, Mateen C.; Langstrom, Bengt; Zaidi, Habib; Vinters, Harry V.; Huang, Sung-Cheng; Satyamurthy, Nagichettiar; Doudet, Doris; Mishani, Eyal; Cohen, Robert M.; Hoilund-Carlsen, Poul F.; Alavi, Abass; Barrio, Jorge R.

    2013-01-01

    The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-beta deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-beta plaques are currently at various stages of FDA approval. However, a

  11. Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid

    OpenAIRE

    Castellani, Rudy J.; Lee, Hyoung-gon; Siedlak, Sandra L.; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A.

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused on amyloid-β as the major pathogenic mechanisms with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectac...

  12. Characterization of Amyloid-β Deposits in Bovine Brains.

    Science.gov (United States)

    Vallino Costassa, Elena; Fiorini, Michele; Zanusso, Gianluigi; Peletto, Simone; Acutis, Pierluigi; Baioni, Elisa; Maurella, Cristiana; Tagliavini, Fabrizio; Catania, Marcella; Gallo, Marina; Faro, Monica Lo; Chieppa, Maria Novella; Meloni, Daniela; D'Angelo, Antonio; Paciello, Orlando; Ghidoni, Roberta; Tonoli, Elisa; Casalone, Cristina; Corona, Cristiano

    2016-02-10

    Amyloid-β (Aβ) deposits are seen in aged individuals of many mammalian species that possess the same aminoacid sequence as humans. This study describes Aβ deposition in 102 clinically characterized cattle brains from animals aged 0 to 20 years. Extracellular and intracellular Aβ deposition was detected with 4G8 antibody in the cortex, hippocampus, and cerebellum. X-34 staining failed to stain Aβ deposits, indicating the non β-pleated nature of these deposits. Western blot analysis and surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry revealed in Tris, Triton, and formic acid fractions the presence of different Aβ peptides, characterized mainly by C-terminally truncated forms. Exploration of the genetic variability of APOE, PSEN1, and PSEN2 genes involved in Alzheimer's disease pathogenesis revealed several previously unreported polymorphisms. This study demonstrates certain similarities between Aβ deposition patterns exhibited in cattle brains and those in the human brain in early stages of aging. Furthermore, the identification of the same Aβ peptides reported in humans, but unable to form aggregates, supports the hypothesis that cattle may be protected against amyloid plaque formation. PMID:26890772

  13. Amyloid imaging in Alzheimer's disease: a literature review.

    Science.gov (United States)

    Saidlitz, P; Voisin, T; Vellas, B; Payoux, P; Gabelle, A; Formaglio, M; Delrieu, J

    2014-07-01

    Therapies targeting amyloid-β peptide currently represent approximately 50% of drugs now being developed for Alzheimer's disease. Some, including active and passive anti-Aβ immunotherapy, directly target the amyloid plaques. The new amyloid tracers are increasingly being included in the proposed updated diagnostic criteria, and may allow earlier diagnosis. Those targeting amyloid-β peptide allow identification of amyloid plaques in vivo. We need to gain insight into all aspects of their application. As florbetapir (Amyvid™) and flutemetamol (Vizamyl™) have received marketing authorization, clinicians require deeper knowledge to be rationally used in diagnosis. In this paper, we review both completed and ongoing observational, longitudinal and interventional studies of these tracers, our main objective being to show the performance of the four most commonly used tracers and their validation. PMID:25226113

  14. Neurobiological probes for specific constituents of senile plaques in aging and Alzheimer's disease

    International Nuclear Information System (INIS)

    Senile plaques are composed of neurites (enlarged axons, nerve terminals, and, possibly, dendrites) associated with focal deposits of amyloid. Plaques are present in small numbers in the amygdala, hippocampus, and neocortex in elderly primates and are abundant in these regions in individuals with Alzheimer's disease. Aged macaques provide a model for investigations of plaques. One of the earliest abnormalities identified in these older animals is multifocal enlargement of individual axons withing the cortex. Later, enlarged neurites appear in clusters (neurite plaques); in mixed plaques, neurites are associated with amyloid. In the oldest animals, many plaques show relatively greater proportions of amyloid. These observations are interpreted to indicate that axonal pathology is an early event and that plaques evolve from the neurite type to the amyloid type. Using antibody probes, we have identified abnormal axons and neurites derived from cholinergic, monoaminergic, and peptidergic systems. These axons and neurites also show accumulations of cytoskeletal antigens, including neurofilament peptides. Similarly, in human tissues, these approaches have identified abnormalities of the cytoskeleton and demonstrated a variety of transmitter-specific antigens in plaques

  15. Scientists Reduce Alzheimer's-Linked Brain Plaques in Mice

    Science.gov (United States)

    ... Jacksonville, Fla. The approach "can be explored for Alzheimer's disease prevention and therapy," he added. Clumps of beta-amyloid proteins, known as plaque, are believed to disrupt brain functioning in people with Alzheimer's disease, the most common form of dementia. The ...

  16. New Insights in the Amyloid-Beta Interaction with Mitochondria

    OpenAIRE

    Carlos Spuch; Saida Ortolano; Carmen Navarro

    2012-01-01

    Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD). Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP) has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both...

  17. Formation of soluble amyloid oligomers and amyloid fibrils by the multifunctional protein vitronectin

    Directory of Open Access Journals (Sweden)

    Langen Ralf

    2008-10-01

    Full Text Available Abstract Background The multifunctional protein vitronectin is present within the deposits associated with Alzheimer disease (AD, age-related macular degeneration (AMD, atherosclerosis, systemic amyloidoses, and glomerulonephritis. The extent to which vitronectin contributes to amyloid formation within these plaques, which contain misfolded, amyloidogenic proteins, and the role of vitronectin in the pathophysiology of the aforementioned diseases is currently unknown. The investigation of vitronectin aggregation is significant since the formation of oligomeric and fibrillar structures are common features of amyloid proteins. Results We observed vitronectin immunoreactivity in senile plaques of AD brain, which exhibited overlap with the amyloid fibril-specific OC antibody, suggesting that vitronectin is deposited at sites of amyloid formation. Of particular interest is the growing body of evidence indicating that soluble nonfibrillar oligomers may be responsible for the development and progression of amyloid diseases. In this study we demonstrate that both plasma-purified and recombinant human vitronectin readily form spherical oligomers and typical amyloid fibrils. Vitronectin oligomers are toxic to cultured neuroblastoma and retinal pigment epithelium (RPE cells, possibly via a membrane-dependent mechanism, as they cause leakage of synthetic vesicles. Oligomer toxicity was attenuated in RPE cells by the anti-oligomer A11 antibody. Vitronectin fibrils contain a C-terminal protease-resistant fragment, which may approximate the core region of residues essential to amyloid formation. Conclusion These data reveal the propensity of vitronectin to behave as an amyloid protein and put forth the possibilities that accumulation of misfolded vitronectin may contribute to aggregate formation seen in age-related amyloid diseases.

  18. The effects of enhanced zinc on spatial memory and plaque formation in transgenic mice

    Science.gov (United States)

    Linkous, D.H.; Adlard, P.A.; Wanschura, P.B.; Conko, K.M.; Flinn, J.M.

    2009-01-01

    There is considerable evidence suggesting that metals play a central role in the pathogenesis of Alzheimer's disease. Reports suggest that elevated dietary metals may both precipitate and potentiate an Alzheimer's disease phenotype. Despite this, there remain few studies that have examined the behavioral consequences of elevated dietary metals in wild type and Alzheimer's disease animals. To further investigate this in the current study, two separate transgenic models of AD (Tg2576 and TgCRND8), together with wild type littermates were administered 10 ppm (0.153 mM) Zn. Tg2576 animals were maintained on a zinc-enriched diet both pre- and postnatally until 11 months of age, while TgCRND8 animals were treated for five months following weaning. Behavioral testing, consisting of "Atlantis" and "moving" platform versions of the Morris water maze, were conducted at the end of the study, and tissues were collected for immunohistochemical analysis of amyloid-β burden. Our data demonstrate that the provision of a zinc-enriched diet potentiated Alzheimer-like spatial memory impairments in the transgenic animals and was associated with reduced hippocampal amyloidplaque deposits. Zinc-related behavioral deficits were also demonstrated in wild type mice, which were sometimes as great as those present in the transgenic animals. However, zinc-related cognitive impairments in transgenic mice were greater than the summation of zinc effects in the wild type mice and the transgene effects.

  19. Influence of hydrophobic Teflon particles on the structure of amyloid beta-peptide

    NARCIS (Netherlands)

    Giacomelli, CE; Norde, W

    2003-01-01

    The amyloid beta-protein (Abeta) constitutes the major peptide component of the amyloid plaque deposits of Alzheimer's disease in humans. The Abeta changes from a nonpathogenic to a pathogenic conformation resulting in self-aggregation and deposition of the peptide. It has been established that dena

  20. Ashwagandha (Withania somnifera reverses β-amyloid1-42 induced toxicity in human neuronal cells: implications in HIV-associated neurocognitive disorders (HAND.

    Directory of Open Access Journals (Sweden)

    Kesava Rao Venkata Kurapati

    Full Text Available Alzheimer's disease (AD is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. At present no curative treatment is available, and research focuses on drugs for slowing disease progression or providing prophylaxis. Withania somnifera (WS also known as 'ashwagandha' is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is a paucity of data on the potential neuroprotective effects of W.somnifera against β-Amyloid (1-42-induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of methanol:Chloroform (3:1 extract of ashwagandha against β-amyloid induced toxicity and HIV-1Ba-L (clade B infection using a human neuronal SK-N-MC cell line. Our results showed that β-amyloid induced cytotoxic effects in SK-N-MC cells as shown by decreased cell growth when tested individually. Also, confocal microscopic analysis showed decreased spine density, loss of spines and decreased dendrite diameter, total dendrite and spine area in clade B infected SK-N-MC cells compared to uninfected cells. However, when ashwagandha was added to β-amyloid treated and HIV-1 infected samples, the toxic effects were neutralized. Further, the MTT cell viability assays and the peroxisome proliferator-activated receptor-γ (PPARγ levels supported these observations indicating the neuroprotective effect of WS root extract against β-amyloid and HIV-1Ba-L (clade B induced neuro-pathogenesis.

  1. Tritium-labeled (E,E)-2,5-Bis(4’-hydroxy-3’-carboxystyryl)benzene as a Probe for β-Amyloid Fibrils

    OpenAIRE

    Matveev, Sergey V.; Kwiatkowski, Stefan; Sviripa, Vitaliy M.; Fazio, Robert C.; Watt, David S.; LeVine, Harry

    2014-01-01

    Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research....

  2. The role of mutated amyloid beta 1-42 stimulating dendritic cells in a PDAPP transgenic mouse

    Directory of Open Access Journals (Sweden)

    LI Jia-lin

    2012-06-01

    Full Text Available Background Amyloid plaque is one of the pathological hallmarks of Alzheimer's disease (AD. Anti-beta-amyloid (Aβ immunotherapy is effective in removing brain Aβ, but has shown to be associated with detrimental effects. To avoid severe adverse effects such as meningoencephalitis induced by amyloid beta vaccine with adjuvant, and take advantage of amyloid beta antibody's therapeutic effect on Alzheimer's disease sufficiently, our group has developed a new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating dendritic cells (DC. Our previous work has confirmed that DC vaccine can induce adequate anti-amyloid beta antibody in PDAPP Tg mice safely and efficiently. The DC vaccine can improve impaired learning and memory in the Alzheimer's animal model, and did not cause microvasculitis, microhemorrhage or meningoencephalitis in the animal model. However, the exact mechanism of immunotherapy which reduces Aβ deposition remains unknown. In this report, we studied the mechanism of the vaccine, thinking that this may have implications for better understanding of the pathogenesis of Alzheimer's disease. Methods A new Alzheimer vaccine with mutated amyloid beta 1-42 peptide stimulating DC which were obtained from C57/B6 mouse bone marrow was developed. Amyloid beta with Freund's adjuvant was inoculated at the same time to act as positive control. After the treatment was done, the samples of brains were collected, fixed, cut. Immunohistochemical staining was performed to observe the expression of the nuclear hormone liver X receptor (LXR, membrane-bound protein tyrosine phosphatase (CD45, the ATP-binding cassette family of active transporters (ABCA1, receptor for advanced glycation end products (RAGE, β-site APP-cleaving enzyme (BACE and Aβ in mouse brain tissue. Semi-quantitative analysis was used to defect CA1, CA2, CA3, DG, Rad in hippocampus region and positive neuron in cortex region. Results Aβ was significantly reduced in the

  3. A peptide study of the relationship between the collagen triple-helix and amyloid

    OpenAIRE

    Parmar, Avanish S.; Nunes, Ana Monica; Baum, Jean; Brodsky, Barbara

    2012-01-01

    Type XXV collagen, or Collagen-Like Amyloidogenic Component (CLAC), is a component of amyloid plaques, and recent studies suggest this collagen affects amyloid fibril elongation and has a genetic association with Alzheimer’s disease. The relationship between the collagen triple helix and amyloid fibrils was investigated by studying peptide models, including a very stable triple helical peptide (Pro-Hyp-Gly)10; an amyloidogenic peptide GNNQQNY; and a hybrid peptide where the GNNQQNY sequence w...

  4. Amyloid β protein and Alzheimer disease

    OpenAIRE

    Square, D

    1997-01-01

    Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view o...

  5. β-淀粉样肽对线粒体的损伤及其在阿尔茨海默病中的作用%Mitochondria injury by amyloid-β peptide and it's function in Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    杨秀明

    2012-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease, which characterized by extracellular amyloid-β peptide (Aβ) plaques and intracellular neurofibrillary tangles(NFTs). The etiological factors and pathogenesis are still unclear. Amyloid-β peptide locates in mitochondria and it can induce a series of disorders in mitochondrial function, such as decreasing in ATP production, promoting oxidative stress, brokening the balance of mitochondrial fission/fusion and enhancing cellular apoptosis, and so on.%阿尔茨海默病(Alzheimer′s disease,AD)是以老年斑(senile plaque,SP)和神经纤维缠结(neurofibrillary tangles,NFTs)为主要病理特征的中枢神经系统退行性疾病,其病因及发病机制至今仍不明确.AD的病变产物β-淀粉样肽(amyloid-βpeptide,Aβ)在线粒体内沉积导致线粒体功能障碍,如ATP产生减少、氧化应激增强、细胞凋亡增强以及线粒体分裂/融合异常等,进而引起AD的一系列病理变化.

  6. The biochemical aftermath of anti-amyloid immunotherapy

    Directory of Open Access Journals (Sweden)

    Nicoll James AR

    2010-10-01

    Full Text Available Abstract Background Active and passive immunotherapy in both amyloid-beta precursor protein (APP transgenic mice and Alzheimer's Disease (AD patients have resulted in remarkable reductions in amyloid plaque accumulation, although the degree of amyloid regression has been highly variable. Nine individuals with a clinical diagnosis of AD dementia were actively immunized with the Aβ peptide 1-42 (AN-1792 and subjected to detailed postmortem biochemical analyses. These patients were compared to 6 non-immunized AD cases and 5 non-demented control (NDC cases. Results All patients were assessed for the presence of AD pathology including amyloid plaques, neurofibrillary tangles and vascular amyloidosis. This effort revealed that two immunotherapy recipients had dementia as a consequence of diseases other than AD. Direct neuropathological examination consistently demonstrated small to extensive areas in which amyloid plaques apparently were disrupted. Characterization of Aβ species remnants by ELISA suggested that total Aβ levels may have been reduced, although because the amounts of Aβ peptides among treated individuals were extremely variable, those data must be regarded as tentative. Chromatographic analysis and Western blots revealed abundant dimeric Aβ peptides. SELDI-TOF mass spectrometry demonstrated a substantive number of Aβ-related peptides, some of them with elongated C-terminal sequences. Pro-inflammatory TNF-α levels were significantly increased in the gray matter of immunized AD cases compared to the NDC and non-immunized AD groups. Conclusions Immunotherapy responses were characterized by extreme variability. Considering the broad range of biological variation that characterizes aging and complicates the recognition of reliable AD biomarkers, such disparities will make the interpretation of outcomes derived from epidemiologic and therapeutic investigations challenging. Although in some cases the apparent removal of amyloid plaques

  7. Interaction between Amyloid-β Pathology and Cortical Functional Columnar Organization

    OpenAIRE

    Beker, Shlomit; Kellner, Vered; Kerti, Lucia; Stern, Edward A

    2012-01-01

    Amyloidplaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of pl...

  8. Genes contributing to prion pathogenesis

    DEFF Research Database (Denmark)

    Tamgüney, Gültekin; Giles, Kurt; Glidden, David V;

    2008-01-01

    incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes...... show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and...

  9. Adolescent exposure to MDMA induces dopaminergic toxicity in substantia nigra and potentiates the amyloid plaque deposition in the striatum of APPswe/PS1dE9 mice.

    Science.gov (United States)

    Abad, Sonia; Ramon, Carla; Pubill, David; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2016-09-01

    MDMA is one of the most used drugs by adolescents and its consumption has been associated with many psychobiological problems, among them psychomotor problems. Moreover, some authors described that early exposure to MDMA may render the dopaminergic neurons more vulnerable to the effects of future neurotoxic insults. Alzheimer disease (AD) is the main cause of dementia in the elderly and a percentage of the patients have predisposition to suffer nigrostriatal alterations, developing extrapyramidal signs. Nigrostriatal dysfunction in the brain of aged APPswe/PS1dE9 (APP/PS1), a mouse model of familiar AD (FAD), has also been described. The aim of the present study was to investigate the consequences of adolescent exposure to MDMA in APP/PS1 mice, on nigrostriatal function on early adulthood. We used a MDMA schedule simulating weekend binge abuse of this substance. Our MDMA schedule produced a genotype-independent decrease in dopaminergic neurons in the substantia nigra that remained at least 3months. Shortly after the injury, wild-type animals showed a decrease in the locomotor activity and apparent DA depletion in striatum, however in the APP/PS1 mice neither the locomotor activity nor the DA levels were modified, but a reduction in dopamine transporter (DAT) expression and a higher levels of oxidative stress were observed. We found that these disturbances are age-related characteristics that this APP/PS1 mice develops spontaneously much later. Therefore, MDMA administration seems to anticipate the striatal dopaminergic dysfunction in this FAD model. The most important outcome lies in a potentiation, by MDMA, of the amyloid beta deposition in the striatum. PMID:27344237

  10. Sustained peripheral depletion of amyloid-β with a novel form of neprilysin does not affect central levels of amyloid-β.

    Science.gov (United States)

    Henderson, Simon J; Andersson, Christin; Narwal, Rajesh; Janson, Juliette; Goldschmidt, Tom J; Appelkvist, Paulina; Bogstedt, Anna; Steffen, Ann-Charlott; Haupts, Ulrich; Tebbe, Jan; Freskgård, Per Ola; Jermutus, Lutz; Burrell, Matthew; Fowler, Susan B; Webster, Carl I

    2014-02-01

    Alzheimer's disease is characterized by the accumulation of amyloid deposits in the brain and the progressive loss of cognitive functions. Although the precise role of amyloid-β in disease progression remains somewhat controversial, many efforts to halt or reverse disease progression have focussed on reducing its synthesis or enhancing its removal. It is believed that brain and peripheral soluble amyloid-β are in equilibrium and it has previously been hypothesized that a reduction in peripheral amyloid-β can lower brain amyloid-β, thereby reducing formation of plaques predominantly composed of insoluble amyloid-β; the so-called peripheral sink hypothesis. Here we describe the use of an amyloid-β degrading enzyme, the endogenous metallopeptidase neprilysin, which is fused to albumin to extend plasma half-life and has been engineered to confer increased amyloid-β degradation activity. We used this molecule to investigate the effect of degradation of peripheral amyloid-β on amyloid-β levels in the brain and cerebrospinal fluid after repeated intravenous dosing for up to 4 months in Tg2576 transgenic mice, and 1 month in rats and monkeys. This molecule proved highly effective at degradation of amyloid-β in the periphery but did not alter brain or cerebrospinal fluid amyloid-β levels, suggesting that the peripheral sink hypothesis is not valid and is the first time that this has been demonstrated in non-human primates. PMID:24259408

  11. Development of Tc-99m Imaging Agents for Abeta Plaques

    International Nuclear Information System (INIS)

    Development of SPECT imaging agents based on Tc-99m targeting Aβ plaques is useful for diagnosis of Alzheimer's disease (AD). A stilbene derivative, [11C]SB-13, showing promise in detecting senile plaques present in AD patients has been reported previously. Based on the 4(prime)-amino-stilbene core structure we have added substituted groups through which a chelating group, N2S2, was conjugated. We report herein a series of Tc-99m labeled stilbene derivative conjugated with a TcO[N2S2] core. The syntheses of stilbenes containing a N2S2 chelating ligand are achieved by a scheme shown. Lipophilic 99mTc stilbene complexes were successfully prepared and purified through HPLC. Preliminary results of in vitro labeling of brain sections from transgenic mice showed very promising plaque labeling. These 99mTc stilbene derivatives are warranted for further evaluations as potential imaging agents targeting amyloid plaques.

  12. Comparative pathobiology of β-amyloid and the unique susceptibility of humans to Alzheimer's disease.

    Science.gov (United States)

    Rosen, Rebecca F; Tomidokoro, Yasushi; Farberg, Aaron S; Dooyema, Jeromy; Ciliax, Brian; Preuss, Todd M; Neubert, Thomas A; Ghiso, Jorge A; LeVine, Harry; Walker, Lary C

    2016-08-01

    The misfolding and accumulation of the protein fragment β-amyloid (Aβ) is an early and essential event in the pathogenesis of Alzheimer's disease (AD). Despite close biological similarities among primates, humans appear to be uniquely susceptible to the profound neurodegeneration and dementia that characterize AD, even though nonhuman primates deposit copious Aβ in senile plaques and cerebral amyloid-β angiopathy as they grow old. Because the amino acid sequence of Aβ is identical in all primates studied to date, we asked whether differences in the properties of aggregated Aβ might underlie the vulnerability of humans and the resistance of other primates to AD. In a comparison of aged squirrel monkeys (Saimiri sciureus) and humans with AD, immunochemical and mass spectrometric analyses indicate that the populations of Aβ fragments are largely similar in the 2 species. In addition, Aβ-rich brain extracts from the brains of aged squirrel monkeys and AD patients similarly seed the deposition of Aβ in a transgenic mouse model. However, the epitope exposure of aggregated Aβ differs in sodium dodecyl sulfate-stable oligomeric Aβ from the 2 species. In addition, the high-affinity binding of (3)H Pittsburgh Compound B to Aβ is significantly diminished in tissue extracts from squirrel monkeys compared with AD patients. These findings support the hypothesis that differences in the pathobiology of aggregated Aβ among primates are linked to post-translational attributes of the misfolded protein, such as molecular conformation and/or the involvement of species-specific cofactors. PMID:27318146

  13. Mechanisms of beta-amyloid neurotoxicity : Perspectives of pharmacotherapy

    NARCIS (Netherlands)

    Harkany, T; Abraham, [No Value; Konya, C; Nyakas, C; Zarandi, M; Penke, B; Luiten, PGM

    2000-01-01

    One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta -amyloid peptides (A beta) in neuritic plaques, Experimental data indicate that different molecular forms of A beta affect a wide array of neuronal and glial functions and ther

  14. Association between Randall's Plaque and Calcifying Nanoparticles

    Science.gov (United States)

    Ciftcioglu, Neva; Vejdani, Kaveh; Lee, Olivia; Mathew, Grace; Aho, Katja M.; Kajander, Olavi; McKay, David S.; Jones, Jeff A.; Hayat, Matthew; Stoller, Marshall L.

    2007-01-01

    Randall's plaques, first described by Alexander Randall in the 1930s, are small subepithelial calcifications in the renal papillae (RP) that also extend deeply into the renal medulla. Despite the strong correlation between the presence of these plaques and the formation of renal stones, the precise origin and pathogenesis of Randall s plaque formation remain elusive. The discovery of calcifying nanoparticles (CNP) and their detection in many calcifying processes of human tissues has raised hypotheses about their possible involvement in renal stone formation. We collected RP and blood samples from 17 human patients who had undergone laparoscopic nephrectomy due to neoplasia. Homogenized RP tissues and serum samples were cultured for CNP. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis were performed on fixed RP samples. Immunohistochemical staining (IHS) was applied on the tissue samples using CNP-specific monoclonal antibody (mAb). Randall s plaques were visible on gross inspection in 11 out of 17 collected samples. Cultures of all serum samples and 13 tissue homogenates had CNP growth within 4 weeks. SEM revealed spherical apatite formations in 14 samples, with calcium and phosphate peaks detected by EDS analysis. IHS was positive in 9 out of 17 samples. A strong link was found between the presence of Randall s plaques and the detection of CNP, also referred to as nanobacteria. These results suggest new insights into the etiology of Randall's plaque formation, and will help us understand the pathogenesis of stone formation. Further studies on this topic may lead us to new approaches on early diagnosis and novel medical therapies of kidney stone formation.

  15. Impact of amyloid imaging on drug development in Alzheimer's disease

    International Nuclear Information System (INIS)

    Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials

  16. 常压高氧对淀粉样蛋白前体/早老素1双重转基因小鼠脑内老年斑及β-淀粉样蛋白的影响%The effect of normobaric hyperoxia on senile plaques and beta-amyloid protein in brain of amyloid protein precursor/presenilin 1 double transgenic mouse

    Institute of Scientific and Technical Information of China (English)

    高宝兵; 龙志敏; 贺桂琼; 孙善全

    2010-01-01

    Objective In order to investigate whether normobaric hyperoxia exert ncumprotective effect on amyloid protein precursor/presenilin 1(APP/PS1)double transgenic Alzheimer's disease(AD) mouse model.Methods Forty APP/PS1 double transgenie mice were randomly divided into 4 groups(A,B,C and D).Mice were treated with 40% oxygen for 8 h per day for 4 weeks in group A and for 8 weeks in group B.Group C and group D were given regular air for 4 weeks and 8 weeks,respectively,as controls.Immunohistochemical staining.Thioflavin S staining.Western blot and ELISA assay were performed on mice brain tissues in all groups after the treatment.Results Immuohistochemical and Thioflavin S staining showed that in hyperoxia-treated mice,number and size of senile plaques in the cerebral cortex and hippocampus were notably decreased,and deposition of AB in the brain of group B decreased more than that of group A.Western blot revealed that in the hyperoxia-treated mice,the levels of C_(99) and C_(83) were greatly increased while the Aβ level notably decreased.compared with controls.However,the expression of holoprotein APP and β-site amyloid cleavage enzyme 1(BACE1)showed no difference among 4 groups.ELISA assay showed that Aβ_(40)((783.6±97.2)pg/m1)and Aβ_(42)((175.3±17.1)pg/ml)were significantly decreased in the brain of 8 weeks hyperoxia-treated mice compared witlI the control group Aβ_(40) ((1251.6±42.3)pg/ml,t=9.36,P<0.01),and A1342((286.8±13.0)pg/ml,t=13.7,P<0.01).Conclusion Treatment with hyperoxia can significantly decrease Aβ levels and lower the number and size of senile plaques in the brain of APP/PS1 transgenic mouse.This study indicates that hyperoxia may exert its neuroprotective effect through decreasing the generation of Aβ or accelerating the clearance of Aβ.%目的 探讨常压高氧(40%O_2,60%空气)处理淀粉样蛋白前体/早老素1(APP/PS1)双重转基因小鼠是否发挥神经保护作用.方法 对APP/PS1双重转基因阿尔茨海默病(AD)模型种

  17. Structural and dynamic study of the transmembrane domain of the amyloid precursor protein.

    Science.gov (United States)

    Nadezhdin, K D; Bocharova, O V; Bocharov, E V; Arseniev, A S

    2011-01-01

    Alzheimer's disease affects people all over the world, regardless of nationality, gender or social status. An adequate study of the disease requires essential understanding of the molecular fundamentals of the pathogenesis. The amyloid β-peptide, which forms amyloid plaques in the brain of people with Alzheimer's disease, is the product of sequential cleavage of a single-span membrane amyloid precursor protein (APP). More than half of the APP mutations found to be associated with familial forms of Alzheimer's disease are located in its transmembrane domain. The pathogenic mutations presumably affect the structural-dynamic properties of the APP transmembrane domain by changing its conformational stability and/or lateral dimerization. In the present study, the structure and dynamics of the recombinant peptide corresponding to the APP fragment, Gln686-Lys726, which comprises the APP transmembrane domain with an adjacent N-terminal juxtamembrane sequence, were determined in the membrane mimetic environment composed of detergent micelles using NMR spectroscopy. The structure obtained in dodecylphosphocholine micelles consists of two α-helices: a short surface-associated juxtamembrane helix (Lys687-Asp694) and a long transmembrane helix (Gly700-Leu723), both connected via a mobile loop region. A minor bend of the transmembrane α-helix is observed near the paired residues Gly708-Gly709. A cholesterol-binding hydrophobic cavity is apparently formed under the loop region, where the juxtamembrane α-helix comes into contact with the membrane surface near the N-terminus of the transmembrane α-helix. PMID:22649674

  18. A New F-18 Labeled PET Agent For Imaging Alzheimer's Plaques

    International Nuclear Information System (INIS)

    Amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD). Advances in development of imaging agents have focused on targeting amyloid plaques. Notable success has been the development of C-11 labeled PIB (Pittsburgh Compound) and a number of studies have demonstrated the utility of this agent. However, the short half life of C-11 (t1/2: 20 min), is a limitation, thus has prompted the development of F-18 labeled agents. Most of these agents are derivatives of amyloid binding dyes; Congo red and Thioflavin. Some of these agents are in clinical trials with encouraging results. We have been exploring new class of agents based on 8-hydroxy quinoline, a weak metal chelator, targeting elevated levels of metals in plaques. Iodine-123 labeled clioquinol showed affinity for amyloid plaques however, it had limited brain uptake and was not successful in imaging in intact animals and humans. We have been successful in synthesizing F-18 labeled 8-hydroxy quinoline. Small animal PET/CT imaging studies with this agent showed high (7-10% ID/g), rapid brain uptake and fast washout of the agent from normal mice brains and delayed washout from transgenic Alzheimer's mice. These promising results encouraged us in further evaluation of this class of compounds for imaging AD plaques.

  19. Magnetite-Amyloid-β deteriorates activity and functional organization in an in vitro model for Alzheimer’s disease

    OpenAIRE

    Sara Teller; Islam Bogachan Tahirbegi; Mònica Mir; Josep Samitier; Jordi Soriano

    2015-01-01

    The understanding of the key mechanisms behind human brain deterioration in Alzheimer’ disease (AD) is a highly active field of research. The most widespread hypothesis considers a cascade of events initiated by amyloid-β peptide fibrils that ultimately lead to the formation of the lethal amyloid plaques. Recent studies have shown that other agents, in particular magnetite, can also play a pivotal role. To shed light on the action of magnetite and amyloid-β in the deterioration of neuronal ci...

  20. A new mechanism found for the pathogenesis of Alzheimer's

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    @@ After many years research,CAS scientists recently identified a new pathway underlying the Alzheimer's disease.They discovered that activation of a protein called β2-adrenergic receptor may lead to the abnormal formation of the amyloid plaques, which are believed to be the hallmark and primary cause of the disease. Their work was reported by Nature Medicine online on 19 November.

  1. Intravenous Delivery of Targeted Liposomes to Amyloid-β Pathology in APP/PSEN1 Transgenic Mice

    OpenAIRE

    Tanifum, Eric A.; Dasgupta, Indrani; Srivastava, Mayank; Bhavane, Rohan C.; Sun, Li; Berridge, John; Pourgarzham, Hoda; Kamath, Rashmi; Espinosa, Gabriela; Cook, Stephen C; Eriksen, Jason L.; ANNAPRAGADA, ANANTH

    2012-01-01

    Extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles constitute the major neuropathological hallmarks of Alzheimer’s disease (AD). It is now apparent that parenchymal Aβ plaque deposition precedes behavioral signs of disease by several years. The development of agents that can target these plaques may be useful as diagnostic or therapeutic tools. In this study, we synthesized an Aβ-targeted lipid conjugate, incorporated it in stealth liposomal nanoparticles and teste...

  2. Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model.

    Science.gov (United States)

    Liao, Fan; Zhang, Tony J; Mahan, Thomas E; Jiang, Hong; Holtzman, David M

    2015-07-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid β (Aβ) in the brain plays a key role in the pathogenesis of AD and that Aβ aggregation is a concentration dependent process. Recently, it was found that Aβ levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF Aβ is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF Aβ levels, and chronic sleep deprivation significantly increased Aβ plaque formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF Aβ levels in APPswe/PS1ΔE9 (PS1APP) transgenic mice that overexpress mutant forms of APP and PSEN1 that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF Aβ and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF Aβ. The diurnal fluctuation of ISF Aβ in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PS1APP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in Aβ accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against Aβ deposition. PMID:25218899

  3. First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.

    Science.gov (United States)

    Cummings, Damian M; Liu, Wenfei; Portelius, Erik; Bayram, Sevinç; Yasvoina, Marina; Ho, Sui-Hin; Smits, Hélène; Ali, Shabinah S; Steinberg, Rivka; Pegasiou, Chrysia-Maria; James, Owain T; Matarin, Mar; Richardson, Jill C; Zetterberg, Henrik; Blennow, Kaj; Hardy, John A; Salih, Dervis A; Edwards, Frances A

    2015-07-01

    Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly

  4. Imaging unstable plaque.

    Science.gov (United States)

    Sriranjan, Rouchelle S; Tarkin, Jason M; Evans, Nicholas R; Chowdhury, Mohammed M; Rudd, James H

    2016-09-01

    Recent advances in imaging technology have enabled us to utilise a range of diagnostic approaches to better characterise high-risk atherosclerotic plaque. The aim of this article is to review current and emerging techniques used to detect and quantify unstable plaque in the context of large and small arterial systems and will focus on both invasive and non-invasive imaging techniques. While the diagnosis of clinically relevant atherosclerosis still relies heavily on anatomical assessment of arterial luminal stenosis, evolving multimodal cross-sectional imaging techniques that encompass novel molecular probes can provide added information with regard to plaque composition and overall disease burden. Novel molecular probes currently being developed to track precursors of plaque rupture such as inflammation, micro-calcification, hypoxia and neoangiogenesis are likely to have translational applications beyond diagnostics and have the potential to play a part in quantifying early responses to therapeutic interventions and more accurate cardiovascular risk stratification. PMID:27273430

  5. Clinical use of amyloid-positron emission tomography neuroimaging: Practical and bioethical considerations.

    Science.gov (United States)

    Witte, Michael M; Foster, Norman L; Fleisher, Adam S; Williams, Monique M; Quaid, Kimberly; Wasserman, Michael; Hunt, Gail; Roberts, J Scott; Rabinovici, Gil D; Levenson, James L; Hake, Ann Marie; Hunter, Craig A; Van Campen, Luann E; Pontecorvo, Michael J; Hochstetler, Helen M; Tabas, Linda B; Trzepacz, Paula T

    2015-09-01

    Until recently, estimation of β-amyloid plaque density as a key element for identifying Alzheimer's disease (AD) pathology as the cause of cognitive impairment was only possible at autopsy. Now with amyloid-positron emission tomography (amyloid-PET) neuroimaging, this AD hallmark can be detected antemortem. Practitioners and patients need to better understand potential diagnostic benefits and limitations of amyloid-PET and the complex practical, ethical, and social implications surrounding this new technology. To complement the practical considerations, Eli Lilly and Company sponsored a Bioethics Advisory Board to discuss ethical issues that might arise from clinical use of amyloid-PET neuroimaging with patients being evaluated for causes of cognitive decline. To best address the multifaceted issues associated with amyloid-PET neuroimaging, we recommend this technology be used only by experienced imaging and treating physicians in appropriately selected patients and only in the context of a comprehensive clinical evaluation with adequate explanations before and after the scan. PMID:27239516

  6. Association between Randall's Plaque and Calcifying Nanoparticles

    Science.gov (United States)

    Citfcioglu, Neva; Vejdani, Kaveh; Lee, Olivia; Mathew, Grace; Aho, Katja M.; Kajander, Olavi; McKay, David S.; Jones, Jeffrey A.; Feiveson, Alan H.; Stoller, Marshall L.

    2007-01-01

    Randall initially described calcified subepithelial papillary plaques, which he hypothesized as nidi for kidney stone formation. The discovery of calcifying nanoparticles (CNP) in many calcifying processes of human tissues has raised another hypothesis about their possible involvement in urinary stone formation. This research is the first attempt to investigate the potential association of these two hypotheses. We collected renal papilla and blood samples from 17 human patients who had undergone laparoscopic nephrectomy due to neoplasia. Immunohistochemical staining (IHS) was applied on the tissue samples using monoclonal antibody 8D10 (mAb) against CNP. Homogenized papillary tissues and serum samples were cultured for CNP. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis were performed on fixed papillary samples. Randall's plaques were visible on gross inspection in 11 out of 17 collected samples. IHS was positive for CNP antigen in 8 of these 11 visually positive samples, but in only 1 of the remaining 6 samples. SEM revealed spherical apatite formations in 14 samples, all of which had calcium and phosphate peaks detected by EDS analysis. From this study, there was some evidence of a link between the presence of Randall's plaques and the detection of CNP, also referred to as nanobacteria. Although causality was not demonstrated, these results suggest that further studies with negative control samples should be made to explore the etiology of Randall's plaque formation, thus leading to a better understanding of the pathogenesis of stone formation.

  7. Generation of amyloid-β is reduced by the interaction of calreticulin with amyloid precursor protein, presenilin and nicastrin.

    Directory of Open Access Journals (Sweden)

    Nina Stemmer

    Full Text Available Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin. Co-immunoprecipitation confirmed that calreticulin is not only associated with amyloid precursor protein but also with the γ-secretase complex members presenilin and nicastrin. Calreticulin was detected at the cell surface by surface biotinylation of cells overexpressing amyloid precursor protein and was co-localized by immunostaining with amyloid precursor protein and presenilin at the cell surface of hippocampal neurons. The P-domain of calreticulin located between the N-terminal N-domain and the C-domain interacts with presenilin, the catalytic subunit of the γ-secretase complex. The P- and C-domains also interact with nicastrin, another functionally important subunit of this complex. Transfection of amyloid precursor protein overexpressing cells with full-length calreticulin leads to a decrease in amyloid-β42 levels in culture supernatants, while transfection with the P-domain increases amyloid-β40 levels. Similarly, application of the recombinant P- or C-domains and of a synthetic calreticulin peptide comprising amino acid 330-344 to amyloid precursor protein overexpressing cells result in elevated amyloid-β40 and amyloid-β42 levels, respectively. These findings indicate that the interaction of

  8. Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease

    International Nuclear Information System (INIS)

    Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [11C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds.

  9. Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

    NARCIS (Netherlands)

    Lee, Jiyeon; Retamal, Claudio; Cuitino, Loreto; Caruano-Yzermans, Amy; Shin, Jung-Eun; van Kerkhof, Peter; Marzolo, Maria-Paz; Bu, Guojun

    2008-01-01

    Accumulation of extracellular amyloid beta peptide (A beta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of A beta from APP is greatly affected by the subcellular loca

  10. Plaque regression and plaque stabilisation in cardiovascular diseases

    Directory of Open Access Journals (Sweden)

    Tarun Dave

    2013-01-01

    Full Text Available Atherosclerosis is characterized by formation of plaques on the inner walls of arteries that threatens to become the leading cause of death worldwide via its sequelae of myocardial infarction and stroke. Endothelial dysfunction leads to cholesterol uptake and accumulation of infl ammatory markers within the plaque. The stability of a plaque eventually depends on the balance between vascular smooth muscle cells that stabilize it and the infl ammatory cells like macrophages and T lymphocytes that make it prone to rupture. The current approach to manage atherosclerosis focuses on the treatment of a ruptured plaque and efforts have been made to reduce the risk of plaque rupture by identifying vulnerable plaques and treating them before they precipitate into clinical events. New diagnostic approaches such as IVUS and CIMT ultrasound are now being preferred over traditional coronary angiography because of their better accuracy in measuring plaque volume rather than the level of stenosis caused. The present review highlights the literature available on two prevalent approaches to manage a vulnerable plaque, namely, plaque stabilization and plaque regression, and their validation through various treatment modalities in recent plaque management studies. Plaque stabilization focuses on stabilizing the content of plaque and strengthening the overlying endothelium, while plaque regression focuses on the overall reduction in plaque volume and to reverse the arterial endothelium to its normal functional state. Although earlier studies contemplated the practicality of plaque regression and focused greatly on stabilization of a vulnerable plaque, our review indicated that, aided by the use of superior diagnostics tools, more intensive lipid modifying therapies have resulted in actual plaque regression.

  11. Efflux transport of serum amyloid P component at the blood–brain barrier

    OpenAIRE

    Veszelka, Szilvia; Laszy, Judit; Pázmány, Tamás; Németh, László; Obál, Izabella; Fábián, László; Szabó, Gábor; Ábrahám, Csongor S.; Deli, Mária A.; Urbányi, Zoltán

    2013-01-01

    Serum amyloid P component (SAP), a member of the innate immune system, does not penetrate the brain in physiological conditions; however, SAP is a stabilizing component of the amyloid plaques in neurodegenerative diseases. We investigated the cerebrovascular transport of human SAP in animal experiments and in culture blood–brain barrier (BBB) models. After intravenous injection, no SAP could be detected by immunohistochemistry or ELISA in healthy rat brains. Salmonella typhi...

  12. Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

    OpenAIRE

    Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

    2013-01-01

    Alzheimer’s disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising ta...

  13. Migraine Pathogenesis

    Institute of Scientific and Technical Information of China (English)

    Nabih M. M.D. Ramadan

    2000-01-01

    @@Introduction Various theories of migraine pathogenesis have been developed over the years. To this date, none fully explains all the migraine phenomena. A complete description of each proposed theory is beyond the scope of this chapter. Nonetheless, a brief description of the arguments for and against the leading theories is noteworthy

  14. Small molecule agents that target amyloid-β aggregation in Alzheimer's disease

    OpenAIRE

    Jones, Michael Roy

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia and currently there is no cure. AD is characterized by the formation of two pathological hallmarks; aggregated forms of the amyloid-β (Aβ) peptide called Aβ plaques and hyperphosphorylated tau proteins, called neurofibrillary tangles (NFT). Aβ is enzymatically cleaved from the amyloid precursor protein (APP) to afford a 38-43 amino acid residue peptide with Aβ1-40 and Aβ1-42 being the most common. Plaque deposits have been shown to ...

  15. Infectious agents in coronary atheromas: a possible role in the pathogenesis of plaque rupture and acute myocardial infarction Agentes infecciosos em ateromas coronarianos: um possível papel na patogênese da ruptura da placa e infarto agudo do miocárdio

    OpenAIRE

    Maria de Lourdes HIGUCHI; Jose A. F. RAMIRES

    2002-01-01

    In this review we report our recent findings of histopathological features of plaque instability and the association with Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP) infection, studying thrombosed coronary artery segments (CAS) of patients who died due to acute myocardial infarction. Vulnerable plaques are known to be associated with fat atheromas and inflammation of the plaque. Here we demonstrated that vulnerability is also related with focal positive vessel remodeling that mai...

  16. Dental plaque identification at home

    Science.gov (United States)

    ... your teeth. Plaque is the major cause of tooth decay and gum disease ( gingivitis ). It is hard to ... the plaque is not removed, it can cause tooth decay or cause the gums to bleed easily (gingivitis) ...

  17. Novel β-amyloid aggregation inhibitors possessing a turn mimic.

    Science.gov (United States)

    Hamada, Yoshio; Miyamoto, Naoko; Kiso, Yoshiaki

    2015-04-01

    Amyloid β peptide, the main component of senile plaques found in the brain of Alzheimer disease (AD) patients, is a molecular target for AD therapeutic intervention. A number of potential AD therapeutics have been reported, including inhibitors of β-secretase, γ-secretase, and Aβ aggregation, and anti-amyloid agents, such as neprilysin, insulin degrading enzyme (IDE), and Aβ antibodies. Recently, we reported potent small-sized β-secretase (BACE1) inhibitors, which could serve as anti-AD drugs. However AD is a progressive disorder, where dementia symptoms gradually worsen over several decades, and therefore may require many years to get cured. One possible way to achieve a greater therapeutic effect is through simultaneous administration of multiple drugs, similar to those used in Highly Active Anti-Retroviral Therapy (HAART) used to treat AIDS. In order to overcome AD, we took a drug discovery approach to evaluate, novel β-amyloid aggregation inhibitors. Previously, we reported that a tong-type compound possessing a turn mimic as the inhibitor of HIV-1 protease dimerization. Oligomerized amyloid β peptides contain a turn structure within the molecule. Here, we designed and synthesized novel β-amyloid aggregation inhibitors with a turn-mimic template, based on the turn conformer of the oligomerized amyloid β peptides. PMID:25736996

  18. Laser-Induced In-Source Decay Applied to the Determination of Amyloid-Beta in Alzheimer's Brains.

    Science.gov (United States)

    Kelley, Andrea R; Perry, George; Castellani, Rudolph J; Bach, Stephan B H

    2016-03-16

    A method for the analysis of amyloid-beta peptides in isolated plaques and intact tissue sections affected by Alzheimer's disease (AD) is presented. This method employs matrix-assisted laser desorption/ionization (MALDI) time-of-flight mass spectrometry and the inherent laser-induced in-source decay (ISD) that occurs coupled with imaging mass spectrometry (IMS) to investigate the composition of these samples eliminating the need for other confirmational MS/MS techniques. These results demonstrate this technique's usefulness for the identification of amyloid-beta peptides in tissue and isolated senile plaques from AD patients using the reproducible fragmentation pattern demonstrated via the laser-induced ISD of synthetic amyloid-beta peptide clips (1-40, 1-42). Clear differences between the hippocampal AD tissue and the control hippocampal tissue regarding the presence of amyloid-beta have been identified. These are based on laser-induced ISD of standard amyloid-beta clips as controls as well as the analysis of isolated senile plaques as a confirmation before tissue analysis. Using the resulting observed peptide clip masses from the control data, we present mass spectrometry based identification of the amyloid-beta peptides in both isolated plaques and hippocampal regions of those patients diagnosed with AD. PMID:26720297

  19. Metal exposure and Alzheimer's pathogenesis.

    Science.gov (United States)

    Liu, Guijian; Huang, Weidong; Moir, Robert D; Vanderburg, Charles R; Lai, Barry; Peng, Zicheng; Tanzi, Rudolph E; Rogers, Jack T; Huang, Xudong

    2006-07-01

    With the growing aging population in Western countries, Alzheimer's disease (AD) has become a major public health concern. No preventive measure and effective treatment for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data strongly suggest that Abeta amyloidosis, which originates from the amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon the age-dependent cerebral Abeta amyloidogenesis are not well recognized. Growing data indicate that cerebral dysregulation of biometals, environmental metal exposure, and oxidative stress contribute to AD pathology. Herein we provided further evidence that both metals (such as Cu) and H(2)O(2) promote formation of neurotoxic Abeta oligomers. Moreover, we first demonstrated that laser capture microdissection coupled with X-ray fluorescence microscopy can be applied to determine elemental profiles (S, Fe, Cu, and Zn) in Abeta amyloid plaques. Clearly the fundamental biochemical mechanisms linking brain biometal metabolism, environmental metal exposure, and AD pathophysiology warrant further investigation. Nevertheless, the study of APP and Abeta metallobiology may identify potential targets for therapeutic intervention and/or provide diagnostic methods for AD. PMID:16503166

  20. Phosphorylation modifies the molecular stability of β-amyloid deposits

    Science.gov (United States)

    Rezaei-Ghaleh, Nasrollah; Amininasab, Mehriar; Kumar, Sathish; Walter, Jochen; Zweckstetter, Markus

    2016-04-01

    Protein aggregation plays a crucial role in neurodegenerative diseases. A key feature of protein aggregates is their ubiquitous modification by phosphorylation. Little is known, however, about the molecular consequences of phosphorylation of protein aggregates. Here we show that phosphorylation of β-amyloid at serine 8 increases the stability of its pathogenic aggregates against high-pressure and SDS-induced dissociation. We further demonstrate that phosphorylation results in an elevated number of hydrogen bonds at the N terminus of β-amyloid, the region that is critically regulated by a variety of post-translational modifications. Because of the increased lifetime of phosphorylated β-amyloid aggregates, phosphorylation can promote the spreading of β-amyloid in Alzheimer pathogenesis. Our study suggests that regulation of the molecular stability of protein aggregates by post-translational modifications is a crucial factor for disease progression in the brain.

  1. The amyloid precursor protein – a novel player within the molecular array of presynaptic nanomachines

    Directory of Open Access Journals (Sweden)

    Melanie Lassek

    2016-01-01

    Full Text Available More than 20 years ago the amyloid precursor protein (APP was identified as the precursor protein of the Aβ peptide, the main component of senile plaques in brains affected by Alzheimer´s disease. The pathophysiology of AD, characterized by a massive loss of synapses, cognitive decline, and behavioral changes was in principle attributed to the accumulation of Aβ. Within the last decades, much effort has gone into understanding the molecular basis of the progression of Alzheimer´s disease. However, little is known about the actual physiological function of amyloid precursor proteins. Allocating APP to the proteome of the structurally and functionally dynamic presynaptic active zone highlights APP as a hitherto unknown player within the setting of the presynapse. The molecular array of presynaptic nanomachines comprising the life cycle of synaptic vesicles, exo- and endocytosis, cytoskeletal rearrangements, and mitochondrial activity provides a balance between structural and functional maintenance and diversity. The generation of genetically designed mouse models further deciphered APP as an essential player in synapse formation and plasticity. Deletion of APP causes an age-dependent phenotype: while younger mice revealed almost no physiological impairments, this condition was changed in the elderly mice. Interestingly, the proteomic composition of neurotransmitter release sites already revealed substantial changes at young age. These changes point to a network that incorporates APP into a cluster of nanomachines. Currently, the underlying mechanism of how APP acts within these machines is still elusive. Within the scope of this review, we shall construct a network of APP interaction partners within the presynaptic active zone. Furthermore, we intend to outline how deletion of APP affects this network during space and time leading to impairments in learning and memory. These alterations may provide a molecular link to the pathogenesis of

  2. SERF Protein Is a Direct Modifier of Amyloid Fiber Assembly

    Directory of Open Access Journals (Sweden)

    S. Fabio Falsone

    2012-08-01

    Full Text Available The inherent cytotoxicity of aberrantly folded protein aggregates contributes substantially to the pathogenesis of amyloid diseases. It was recently shown that a class of evolutionary conserved proteins, called MOAG-4/SERF, profoundly alter amyloid toxicity via an autonomous but yet unexplained mode. We show that the biological function of human SERF1a originates from its atypical ability to specifically distinguish between amyloid and nonamyloid aggregation. This inherently unstructured protein directly affected the aggregation kinetics of a broad range of amyloidogenic proteins in vitro, while being inactive against nonamyloid aggregation. A representative biophysical analysis of the SERF1a:α-synuclein (aSyn complex revealed that the amyloid-promoting activity resulted from an early and transient interaction, which was sufficient to provoke a massive increase of soluble aSyn amyloid nucleation templates. Therefore, the autonomous amyloid-modifying activity of SERF1a observed in living organisms relies on a direct and dedicated manipulation of the early stages in the amyloid aggregation pathway.

  3. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  4. Clinical and pathological study on 10 cases of cerebral lobe hemorrhage related with cerebral amyloid angiopathy

    Directory of Open Access Journals (Sweden)

    Xiao-qi LI

    2015-07-01

    Full Text Available Objective To summarize the clinical data and pathological features of 10 cases of cerebral lobar hemorrhage related with cerebral amyloid angiopathy (CAA diagnosed pathologically, thereby to improve the knowledge and diagnosis of the disease. Methods The clinical data of 10 cases of cerebral lobar hemorrhage related with CAA, collected in the General Hospital of Shenyang Command from 1983 up to now, were retrospectively analyzed, and the clinical and neuropathological features of these cases were summarized. Results Of the 10 patients, 2 suffered from single lobar hemorrhage and 8 multiple lobar hemorrhage, all of them were confirmed pathologically to have ruptured into the subarachnoid space. Pathological examination revealed microaneurysm in 2 cases, "double barrel" change in 4 cases, multiple arteriolar clusters in 5 cases, obliterative onion-liked intima change in 4 cases, and fibrinoid necrosis of vessel wall in 7 cases. In addition, neurofibrillary tangles were found in 8 cases, and senile plaque was observed in 5 cases. Conclusions Cerebral lobar hemorrhage related with CAA is mainly located in the parietal, temporal and occipital lobes, readily breaking into the subarachnoid space, and it is often multiple and recurrent. The CAA associated microvasculopathy was found frequently in the autopsy sample of CAA related cerebral lobar hemorrhage, and it may contribute to the pathogenesis of cerebral hemorrhage. DOI: 10.11855/j.issn.0577-7402.2015.07.04

  5. Protective effects of pinostrobin on β-amyloid-induced neurotoxicity in PC12 cells.

    Science.gov (United States)

    Xian, Yan-Fang; Ip, Siu-Po; Lin, Zhi-Xiu; Mao, Qing-Qiu; Su, Zi-Ren; Lai, Xiao-Ping

    2012-11-01

    Beta-Amyloid peptide (Aβ), a major protein component of brain senile plaques in Alzheimer's disease (AD), has been considered as a critical cause in the pathogenesis of AD. Pinostrobin, a potent flavonoid inducer, is the major and most active ingredient of Folium cajani. The present study aimed to investigate whether pinostrobin could provide protective effect against Aβ(25-35)-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells. The PC12 cells were pretreated with different concentrations of pinostrobin for 2 h, followed by the challenge with 20 μM Aβ(25-35) for 24 h. The results showed that pretreatment with pinostrobin significantly elevated cell viability, decreased the lactate dehydrogenase activity, the levels of intracellular reactive oxygen species and calcium, and mitochondrial membrane potential in Aβ(25-35)-treated PC12 cells. In addition, pinostrobin significantly suppressed the formation of DNA fragmentation and increased the ratio of Bcl-2/Bax. These results indicate that pinostrobin was able to exert a neuroprotective effect against Aβ(25-35)-induced neurotoxicity in PC12 cells, at least in part, via inhibiting oxidative damage and calcium overload, as well as suppressing the mitochondrial pathway of cellular apoptosis. PMID:22565301

  6. β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology

    Institute of Scientific and Technical Information of China (English)

    Xiaosong Liu; Xiaohui Zhao; Xianglu Zeng; Koen Bossers; Dick F Swaab; Jian Zhao; Gang Pei

    2013-01-01

    Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the γ-secretasemediated amyloid-β (Aβ) pathology plays an important role.We found that a multifunctional protein,β-arrestin1,facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature γ-secretase complex through its functional interaction with APH-1.Deficiency of β-arrestin1 or inhibition of binding of β-arrestin1 with APH-1 by small peptides reduced Aβ production without affecting Notch processing.Genetic ablation of β-arrestin1 diminished Aβ pathology and behavioral deficits in transgenic AD mice.Moreover,in brains of sporadic AD patients and transgenic AD mice,the expression of β-arrestin1 was upregulated and correlated well with neuropathological severity and senile Aβ plaques.Thus,our study identifies a regulatory mechanism underlying both γ-secretase assembly and AD pathogenesis,and indicates that specific reduction of Aβ pathology can be achieved by regulation of the γ-secretase assembly.

  7. Prevalence of Foam Cells and Helper-T cells in Atherosclerotic Plaques of Korean Patients with Carotid Atheroma

    OpenAIRE

    Lee, Won-Ha; Ko, Young-Hyeh; Kim, Dong-Ik; Lee, Byung-Boong; Park, Jeong-Euy

    2000-01-01

    Background Inflammation and activation of immune cells have important roles in the pathogenesis of atherosclerosis. We analyzed the involvement of various immune cells in the pathogenesis of atherosclerosis. Methods We investigated the presence of foam cells, lymphocytes and killer cells in 11 atherosclerotic plaque specimens removed from Korean patients who underwent carotid endoarterectomy. Atherosclerotic plaques were analyzed by immunohistochemistry using monoclonal antibody specific to f...

  8. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy

    OpenAIRE

    Zotova, Elina; Nicoll, James A. R.; Kalaria, Raj; Holmes, Clive; Boche, Delphine

    2010-01-01

    Evidence for the involvement of inflammatory processes in the pathogenesis of Alzheimer's disease (AD) has been documented for a long time. However, the inflammation hypothesis in relation to AD pathology has emerged relatively recently. Even in this hypothesis, the inflammatory reaction is still considered to be a downstream effect of the accumulated proteins (amyloid beta (Abeta) and tau). This review aims to highlight the importance of the immune processes involved in AD pathogenesis based...

  9. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model

    Science.gov (United States)

    Li, Tong; Braunstein, Kerstin E.; Zhang, Juhong; Lau, Ashley; Sibener, Leslie; Deeble, Christopher; Wong, Philip C.

    2016-01-01

    A central question in Alzheimer's Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau. PMID:27373369

  10. Impact of amyloid imaging on drug development in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Mathis, Chester A. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)], E-mail: mathisca@upmc.edu; Lopresti, Brian J. [Department of Radiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Klunk, William E. [Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2007-10-15

    Imaging agents capable of assessing amyloid-beta (A{beta}) content in vivo in the brains of Alzheimer's disease (AD) subjects likely will be important as diagnostic agents to detect A{beta} plaques in the brain as well as to help test the amyloid cascade hypothesis of AD and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several A{beta} imaging agents are currently underway. We reported the first PET studies of the carbon 11-labeled thioflavin-T derivative Pittsburgh Compound B in 2004, and this work has subsequently been extended to include a variety of subject groups, including AD patients, mild cognitive impairment patients and healthy controls. The ability to quantify regional A{beta} plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of A{beta} plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.

  11. Ultrasound features of human carotid plaques

    OpenAIRE

    Östling, Gerd

    2013-01-01

    Atherosclerotic plaques in the carotid arteries are common in a middle-aged population. When a carotid plaque ruptures it may result in a cerebrovascular event. However, only a minor part of carotid plaques will eventually rupture. Finding those plaques is essential to decide the most appropriate treatment strategy. With non-invasive ultrasound the carotid plaques can be visualized for assessment of various features. Plaques that appear dark on the ultrasound image, i.e. echolucent plaques...

  12. Alzheimer's disease: neuritic plaques and neurofibrillary tangles in human brain identified by FTIR spectroscopy

    Science.gov (United States)

    Choo, Lin-P'ing; Jackson, Michael; Halliday, William C.; Mantsch, Henry H.

    1994-01-01

    The abnormal abundance of (beta) -amyloid plaques and neurofibrillary tangles are the hallmark of Alzheimer's disease (AD). Human central nervous system (CNS) grey matter was probed for characteristics arising from these pathological features. In AD but not normal grey matter, an IR band at 1615 cm-1 is seen, characteristic of a protein in an aggregated state. We speculate that this band arises from (beta) A4-amyloid protein. AD, and 18q- grey matter spectra show increased intensity of phosphate bands in accordance with known hyperphosphorylation of proteins found in neurofibrillary tangles. These spectral features may be useful in the diagnosis of AD.

  13. Evaluation of the amyloid beta-GFP fusion protein as a model of amyloid beta peptides-mediated aggregation: A study of DNAJB6 chaperone

    OpenAIRE

    Rasha Mohamed Hussein; Rashed, Laila A

    2015-01-01

    Alzheimer’s disease is a progressive neurodegenerative disease characterized by the accumulation and aggregation of extracellular amyloid β (Aβ) peptides and intracellular aggregation of hyper-phosphorylated tau protein. Recent evidence indicates that accumulation and aggregation of intracellular amyloid β peptides may also play a role in disease pathogenesis. This would suggest that intracellular Heat Shock Proteins (HSP) that maintain cellular protein homeostasis might be candidates for dis...

  14. Disrupted-in-Schizophrenia-1 Attenuates Amyloid-β Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of β-Site APP-Cleaving Enzyme 1 Levels.

    Science.gov (United States)

    Deng, Qing-Shan; Dong, Xing-Yu; Wu, Hao; Wang, Wang; Wang, Zhao-Tao; Zhu, Jian-Wei; Liu, Chun-Feng; Jia, Wei-Qiang; Zhang, Yan; Schachner, Melitta; Ma, Quan-Hong; Xu, Ru-Xiang

    2016-01-01

    Disrupted-in-Schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of β-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-β (Aβ) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Aβ40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates Aβ generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD. PMID:26062786

  15. Cerebral amyloid angiopathy

    Science.gov (United States)

    ... Fenichel GM, Jankovic J, Mazziotta JC, eds. Bradley's Neurology in Clinical Practice . 6th ed. Philadelphia, PA: Elsevier ... al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68:1411-1416. PMID: 17452586 www.ncbi. ...

  16. Infliximab in the treatment of plaque type psoriasis

    OpenAIRE

    Rosita Saraceno; Andrea Saggini; Lucia Pietroleonardo; Sergio Chimenti

    2009-01-01

    Rosita Saraceno, Andrea Saggini, Lucia Pietroleonardo, Sergio ChimentiDepartment of Dermatology, University of Rome Tor Vergata, Rome, Viale Oxford 81, Rome, ItalyAbstract: Psoriasis is a chronic and immunomediated skin disease characterized by erythematous scaly plaques. Psoriasis affects approximately 1% to 3% of the Caucasian population. Tumor necrosis factor alpha (TNF-α) is a proinflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. Infliximab is an ...

  17. A novel approach to the identification and quantitative elemental analysis of amyloid deposits-Insights into the pathology of Alzheimer's disease

    International Nuclear Information System (INIS)

    There is considerable interest in the role of metals such as iron, copper, and zinc in amyloid plaque formation in Alzheimer's disease. However to convincingly establish their presence in plaques in vivo, a sensitive technique is required that is both quantitatively accurate and avoids isolation of plaques or staining/fixing brain tissue, since these processes introduce contaminants and redistribute elements within the tissue. Combining the three ion beam techniques of scanning transmission ion microscopy, Rutherford back scattering spectrometry and particle induced X-ray emission in conjunction with a high energy (MeV) proton microprobe we have imaged plaques in freeze-dried unstained brain sections from CRND-8 mice, and simultaneously quantified iron, copper, and zinc. Our results show increased metal concentrations within the amyloid plaques compared with the surrounding tissue: iron (85 ppm compared with 42 ppm), copper (16 ppm compared to 6 ppm), and zinc (87 ppm compared to 34 ppm).

  18. The mechanism of the low-density lipoprotein receptor- related protein (LRP) in the production of amyloid-[Beta] peptide

    OpenAIRE

    Chen, Eunice Chungyu

    2008-01-01

    Alzheimer's disease (AD) is the most common form of neurodegenerative disorder affecting the elderly, presenting symptoms such as memory impairment and dementia. AD is pathologically characterized by the development of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The plaques are composed of amyloid-[Beta] peptide (A[Beta]) and the NFTs are composed of a hyperphosphorylated form of the tau protein. A[Beta] is formed by sequential proteolytic processing of the a...

  19. Altered motility of plaque-associated microglia in a model of Alzheimer's disease.

    Science.gov (United States)

    Gyoneva, Stefka; Swanger, Sharon A; Zhang, Jing; Weinshenker, David; Traynelis, Stephen F

    2016-08-25

    Alzheimer's disease (AD), the most common form of dementia in the elderly, is characterized by the presence of extracellular plaques composed of amyloid β (Aβ) peptides and intracellular tau aggregates. The plaques are surrounded by microglia, the brain's resident immune cells, which likely participate in the clearance of Aβ by phagocytosis. The microglia that are associated with plaques display an abnormal ameboid morphology and do not respond to tissue damage, in contrast to microglia in healthy brains. Here, we used time lapse confocal microscopy to perform a detailed real-time examination of microglial motility in acute hippocampal brain slices from the 5xFAD mouse model of AD, which was crossed to Cx3cr1(GFP/GFP) mice to achieve microglia-specific GFP expression for visualization. During baseline conditions, microglia around plaques appeared hypermotile, moving the processes that were pointing away from plaques at higher speed than microglia not associated with plaques. Yet, neither plaque-associated, nor plaque-free microglia were able to extend processes toward sites of modest mechanical damage. Application of the selective adenosine A2A receptor antagonist preladenant, which restores microglial response to cellular damage in a mouse model of Parkinson's disease, reduced the hypermotility of plaque-associated microglia, but did not restore motility toward damaged cells in slices from 5xFAD mice. Our results suggest that process hypermotility and resistance to A2A antagonism during response to tissue damage may represent unique functional phenotypes of plaque-associated microglia that impair their ability to function properly in the AD brain. PMID:27288150

  20. Infliximab in the treatment of plaque type psoriasis

    Directory of Open Access Journals (Sweden)

    Rosita Saraceno

    2009-04-01

    Full Text Available Rosita Saraceno, Andrea Saggini, Lucia Pietroleonardo, Sergio ChimentiDepartment of Dermatology, University of Rome Tor Vergata, Rome, Viale Oxford 81, Rome, ItalyAbstract: Psoriasis is a chronic and immunomediated skin disease characterized by erythematous scaly plaques. Psoriasis affects approximately 1% to 3% of the Caucasian population. Tumor necrosis factor alpha (TNF-α is a proinflammatory cytokine that plays a critical role in the pathogenesis of psoriasis. Infliximab is an anti-TNF-α drug widely used for the treatment of plaque type psoriasis and psoriatic arthritis. Controlled clinical trials demonstrated that infliximab is characterized by a high degree of clinical response in moderate to severe plaque psoriasis. Moreover infliximab showed rapid efficacy in nail psoriasis which represents a therapeutic challenge for dermatologists and a relevant source of distress for patients with plaque psoriasis. This anti-TNF-α has an encouraging safety profile, especially as long as physicians are watchful in prevention and early diagnosis of infections and infuse reactions. The efficacy, tolerability and safety profiles suggest infliximab as a suitable anti-psoriatic drug in the long-term treatment of a chronic disease such as plaque-type psoriasis.Keywords: psoriasis, nail psoriasis, infliximab, long-term treatment

  1. A STUDY ON TOPICAL CALCIUM DOBESILATE FOR THE TREATMENT OF LIMITED PLAQUE PSORIASIS

    Directory of Open Access Journals (Sweden)

    Neerja Puri

    2013-07-01

    Full Text Available Introduction: Topical dobesilate offers the potential for treatment of plaque psoriasis without atrophy or other local side effects associated with the use of topical corticosteroids. Fibroblast growth factor (FGF-mediated pathways participate in many of the cellular events implicated in the pathogenesis of psoriasis. Thus, targeting FGF signals may be potentially therapeutic. Aims: To study the efficacy of topical calcium dobesilate for the treatment of 50 patients of limited plaque psoriasis. Methods: For the present study, fifty clinically diagnosed cases of psoriasis with limited number of plaques ( 0.05.

  2. Positron emission tomography radioligands for in vivo imaging of Aβ plaques

    OpenAIRE

    Mason, N Scott; Mathis, Chester A.; Klunk, William E

    2013-01-01

    The development of positron emission tomography (PET) radioligands for the non-invasive imaging of amyloidplaque burden has been the focus of intense research efforts over the last decade. A variety of structural backbones have been investigated and several radiolabeled molecules have been evaluated in phase I (and later) clinical studies. These efforts have been driven by the desire not only to develop a suitable diagnostic imaging agent but also to develop a means to evaluate potential t...

  3. Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation

    OpenAIRE

    Cherry, Jonathan D.; Olschowka, John A.; O’Banion, M. Kerry

    2015-01-01

    Background Neuroinflammation has long been considered a driver of Alzheimer’s disease progression. However, experiments developed to explore the interaction between neuroinflammation and Alzheimer’s disease (AD) pathology showed a surprising reduction in amyloid beta (Aβ) plaque deposition. We sought to understand this unexpected outcome by examining microglia phenotypes during chronic neuroinflammation. Methods Using an adeno-associated virus vector carrying hIL-1β cDNA, inflammation was ind...

  4. Acute stress increases interstitial fluid amyloid-β via corticotropin-releasing factor and neuronal activity

    OpenAIRE

    Kang, Jae-Eun; Cirrito, John R.; Dong, Hongxin; John G. Csernansky; Holtzman, David M.

    2007-01-01

    Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is critical in the pathogenesis of Alzheimer's disease. Aβ is produced by neurons and released into the brain interstitial fluid (ISF), a process regulated by synaptic activity. To determine whether behavioral stressors can regulate ISF Aβ levels, we assessed the effects of chronic and acute stress paradigms in amyloid precursor protein transgenic mice. Isolation stress over 3 months increased Aβ levels by 84%. ...

  5. Interaction between amyloid-β pathology and cortical functional columnar organization.

    Science.gov (United States)

    Beker, Shlomit; Kellner, Vered; Kerti, Lucia; Stern, Edward A

    2012-08-15

    Amyloidplaques are one of the major neuropathological features in Alzheimer's disease (AD). Plaques are found in the extracellular space of telencephalic structures, and have been shown to disrupt neuronal connectivity. Since the disruption of connectivity may underlie a number of the symptoms of AD, understanding the distribution of plaques in the neuropil in relation to the connectivity pattern of the neuronal network is crucial. We measured the distribution and clustering patterns of plaques in the vibrissae-receptive primary sensory cortex (barrel cortex), in which the cortical columnar structure is anatomically demarcated by boundaries in Layer IV. We found that the plaques are not distributed randomly with respect to the barrel structures in Layer IV; rather, they are more concentrated in the septal areas than in the barrels. This difference was not preserved in the supragranular extensions of the functional columns. When comparing the degree of clustering of plaques between primary sensory cortices, we found that the degree of plaques clustering is significantly higher in somatosensory cortex than in visual cortex, and these differences are preserved in Layers II/III. The degree of areal discontinuity is therefore correlated with the patterns of neuropathological deposits. The discontinuous anatomical structure of this area allows us to make predictions about the functional effects of plaques on specific patterns of computational disruption in the AD brain. PMID:22895708

  6. Amyloid Precursor Protein Processing in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Adwait BHADBHADE

    2012-03-01

    Full Text Available How to Cite this Article: Bhadbhade A, Cheng DW. Amyloid Precursor Protein Processing in Alzheimer’s Disease. Iranian Journal of Child Neurology2012;6(1:1-5.Alzheimer’s disease (AD is a progressive neurodegenerative disorder and a leading cause of dementia. The AD is characterized by presence of intraneuronal tangles and extracellular plaques in the brain. The plaques are composed of dense and mostly insoluble deposits of amyloid beta peptide (Aβ, formed by sequential cleavage of the Amyloid Precursor Protein (APP, by two pathways amyloidogenic and non-amyloidogenic. Tangles are composed of paired helical fragments, which aggregate to form, microtubular protein tau. Although Aβ plaques are established to be the cause of the disease, there exist genetic factors and other pathological identifications in addition to these which are an integral part of the disease. This article gives an overview into the mechanism of APP action, genetic factors and other pathological identifications contributing to Alzheimer’s disease formation.References Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. American Journal of Public Health 1998;88(9:1337. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population. Arch Neurol 2003;60(8:1119-22. Möller HJ, Graeber M. The case described by Alois Alzheimer in 1911. European Archives of Psychiatry and Clinical Neuroscience 1998:248(3:111-122. Selkoe D J. (2002. Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease. J Clinic Investigat 2002;110(10: 1375-82. Wolfe MS. Tau mutations in neurodegenerative diseases. J Biolog Chem 2009;284(10:6021. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiological reviews 2001;81(2:741. Selkoe DJ. The cell biology of [beta]-amyloid precursor protein and presenilin in Alzheimer

  7. β-Amyloid pathogenesis: Chemical properties versus cellular levels

    DEFF Research Database (Denmark)

    Tiwari, Manish Kumar; Kepp, Kasper Planeta

    2016-01-01

    Although genetic Aβ variants cause early-onset Alzheimer's disease, literature reports on Aβ properties are heterogeneous, obscuring molecular mechanisms, as illustrated by recent failures of Aβ-level targeting trials. Thus, we combined available data on Aβ levels and ratios, aggregation propensi...

  8. Amyloid Fibril Solubility.

    Science.gov (United States)

    Rizzi, L G; Auer, S

    2015-11-19

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain-side-chain interactions, backbone hydrogen bonding, and temperature affect amyloid fibril solubility, which might prove to be a powerful tool to design protein fibrils with desired solubility and aggregation properties in general. PMID:26496385

  9. Amyloid Fibril Solubility

    CERN Document Server

    Rizzi, L G

    2015-01-01

    It is well established that amyloid fibril solubility is protein specific, but how solubility depends on the interactions between the fibril building blocks is not clear. Here we use a simple protein model and perform Monte Carlo simulations to directly measure the solubility of amyloid fibrils as a function of the interaction between the fibril building blocks. Our simulations confirms that the fibril solubility depends on the fibril thickness and that the relationship between the interactions and the solubility can be described by a simple analytical formula. The results presented in this study reveal general rules how side-chain side-chain interactions, backbone hydrogen bonding and temperature affect amyloid fibril solubility, which might prove a powerful tool to design protein fibrils with desired solubility and aggregation properties in general.

  10. Beta-protein deposition: a pathogenetic link between Alzheimer's disease and cerebral amyloid angiopathies.

    Science.gov (United States)

    Coria, F; Prelli, F; Castaño, E M; Larrondo-Lillo, M; Fernandez-Gonzalez, J; van Duinen, S G; Bots, G T; Luyendijk, W; Shelanski, M L; Frangione, B

    1988-10-25

    Cerebral amyloid angiopathy (CAA) refers to a group of hereditary (hereditary cerebral hemorrhage with amyloidosis, HCHWA and sporadic (SCAA) disorders characterized by amyloid fibril deposition restricted to the leptomeningeal and cortical vasculature leading to recurrent hemorrhagic and/or ischemic accidents. On clinical and biochemical grounds, two forms of HCHWA can be distinguished. The amyloid subunit of the HCHWA of Icelandic origin is related to Cystatin C, while amyloid from patients of Dutch origin (HCHWA-D) is related to the beta-protein (or A4), the main component of vascular and plaque core amyloid in Alzheimer's disease (AD) and Down's syndrome (DS) [corrected]. SCAA is an increasingly recognized cause of stroke in normotensive individual amounting to 5-10% of all cerebrovascular accidents. We now report the isolation and partial amino acid sequence of the amyloid subunit from a case of SCAA and a new case of HCHWA-D. The recognition that a heterogeneous group of diseases are linked by similar pathological and chemical features suggests that diversity of etiological factors may promote a common pathogenetic mechanism leading to amyloid-beta (A beta) deposition, and open new ways of research in AD and CAA as they are related to dementia and stroke. PMID:3058268

  11. Amyloid-β colocalizes with apolipoprotein B in absorptive cells of the small intestine

    Directory of Open Access Journals (Sweden)

    Dhaliwal Satvinder S

    2009-10-01

    Full Text Available Abstract Background Amyloid-β is recognized as the major constituent of senile plaque found in subjects with Alzheimer's disease. However, there is increasing evidence that in a physiological context amyloid-β may serve as regulating apolipoprotein, primarily of the triglyceride enriched lipoproteins. To consider this hypothesis further, this study utilized an in vivo immunological approach to explore in lipogenic tissue whether amyloid-β colocalizes with nascent triglyceride-rich lipoproteins. Results In murine absorptive epithelial cells of the small intestine, amyloid-β had remarkable colocalization with chylomicrons (Manders overlap coefficient = 0.73 ± 0.03 (SEM, the latter identified as immunoreactive apolipoprotein B. A diet enriched in saturated fats doubled the abundance of both amyloid-β and apo B and increased the overlap coefficient of the two proteins (0.87 ± 0.02. However, there was no evidence that abundance of the two proteins was interdependent within the enterocytes (Pearson's Coefficient Conclusion The findings of this study are consistent with the possibility that amyloid-β is secreted by enterocytes as an apolipoprotein component of chylomicrons. However, secretion of amyloid-β appears to be independent of chylomicron biogenesis.

  12. Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Soumee Bhattacharya

    Full Text Available The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD, providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer's Disease (5XFAD mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis.

  13. Noninvasive carotid plaque characterization by black blood MRI

    International Nuclear Information System (INIS)

    Management of atherosclerotic carotid arteries requires both plaque characterization and determination of the degree of stenosis, especially when carotid stenting (GAS) is being considered for severe carotid stenosis. Recent studies have demonstrated that high-resolution MRI can identify plaque components, such as the lipid-rich necrotic core, intraplaque hemorrhage, fibrous tissue, and the calcification present in human carotid atherosclerosis. The purpose of this study was to assess the feasibility of black blood MRI (BB-MRI) for accurately identifying the plaque components in vivo. Twenty-six consecutive patients scheduled for carotid endarterectomy (CEA) underwent a BB-MRI examination within 2 weeks before the surgical procedure using a 1.5-T Philips scanner with a protocol that generated 2 contrast weightings (T1 and T2). The MR images were acquired using cardiac gating to minimize motion artifact and fat suppression to reduce MR signals from subcutaneous fatty tissue. The plaque evaluations obtained by BB-MRI were compared with the intra-operative video recordings, the excised specimens, and the histological sections. With BB-MRI, the combination of the signal intensities in the T1- and T2- weighted images for each component (lipid deposits, intra-plaque hemorrhage, fibrous plaque, and calcification) showed findings that corresponded with the excised specimens. Complex morphological features could also be assessed by BB-MRI. BB-MRI is a useful method for noninvasively imaging and characterizing atherosclerotic carotid arteries. This MRI technique can provide valuable information that can be used to decide whether to perform a CEA or a GAS in patients with severe carotid stenosis. Furthermore, BB-MRI appears to be a useful tool for the investigation of the pathogenesis and natural history of carotid atherosclerosis. (author)

  14. Disappearance of La Caille Plaque

    Science.gov (United States)

    2010-04-01

    A bronze plaque erected to the memory of N.-L. de La Caille near the site of his observatory in Central Cape Town, has been stolen by metal thieves. It was designed by the famous architect Sir Herbert Baker.

  15. New Insights in the Amyloid-Beta Interaction with Mitochondria

    Directory of Open Access Journals (Sweden)

    Carlos Spuch

    2012-01-01

    Full Text Available Biochemical and morphological alterations of mitochondria may play an important role in the pathogenesis of Alzheimer’s disease (AD. Particularly, mitochondrial dysfunction is a hallmark of amyloid-beta-induced neuronal toxicity in Alzheimer’s disease. The recent emphasis on the intracellular biology of amyloid-beta and its precursor protein (APP has led researchers to consider the possibility that mitochondria-associated and mitochondrial amyloid-beta may directly cause neurotoxicity. Both proteins are known to localize to mitochondrial membranes, block the transport of nuclear-encoded mitochondrial proteins to mitochondria, interact with mitochondrial proteins, disrupt the electron transport chain, increase reactive oxygen species production, cause mitochondrial damage, and prevent neurons from functioning normally. In this paper, we will outline current knowledge of the intracellular localization of amyloid-beta. Moreover, we summarize evidence from AD postmortem brain as well as animal AD models showing that amyloid-beta triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. Thus, this paper supports the Alzheimer cascade mitochondrial hypothesis such as the most important early events in this disease, and probably one of the future strategies on the therapy of this neurodegenerative disease.

  16. Reexamining Alzheimer's disease: evidence for a protective role for amyloid-beta protein precursor and amyloid-beta.

    Science.gov (United States)

    Castellani, Rudy J; Lee, Hyoung-gon; Siedlak, Sandra L; Nunomura, Akihiko; Hayashi, Takaaki; Nakamura, Masao; Zhu, Xiongwei; Perry, George; Smith, Mark A

    2009-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies'' and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition. PMID:19584435

  17. Periodontal pathogens in atheromatous plaque

    Directory of Open Access Journals (Sweden)

    Saroj K. Rath

    2014-01-01

    Full Text Available Background: There has been increasing attention paid in recent years to the possibility that oral bacterial infection, particularly periodontal disease may influence the initiation and or progression of systemic diseases. These studies confirm the observation that heart disease is the most commonly found systemic condition in patients with periodontal disease. Moreover, the literature has also highlighted substantial evidence indicating the presence of Gram-negative periodontal pathogens in atheromatous plaques. Aim: This study intends to investigate the possible association between periodontal health and coronary artery disease by evaluating periodontal status, association between the periodontal plaque and coronary atheromatous plaques for presence of micro-organisms such as, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, and Tannerella forsythia. Materials and methods: A case-control study was designed with seven patients who had undergone coronary endarterectomy for cardiovascular disease and 28 controls. The periodontal examination for cases was performed 1 day before vascular surgery and the controls were clinically examined. The atheromatous plaque sample collected during endarterectomy and the intraoral plaque samples were subjected to polymerase chain reaction for identification of A. actinomycetemcomitans, P. gingivalis, P. intermedia and T. forsythia. Results: The presence of periodontal bacteria DNA in coronary atheromatous plaques and sub-gingival plaque samples of the same patients was confirmed by this study. CONCLUSION A correlation was established between putative bacteria contributing to atheromatous plaques and species associated with periodontal disease. One particularly important study to be carried out is the investigation of a possible clinically meaningful reduction in coronary heart disease resulting from the prevention or treatment of periodontal disease.

  18. Bacterial sex in dental plaque

    OpenAIRE

    Olsen, Ingar; Tribble, Gena D; Fiehn, Nils-Erik; Wang, Bing-Yan

    2013-01-01

    Genes are transferred between bacteria in dental plaque by transduction, conjugation, and transformation. Membrane vesicles can also provide a mechanism for horizontal gene transfer. DNA transfer is considered bacterial sex, but the transfer is not parallel to processes that we associate with sex in higher organisms. Several examples of bacterial gene transfer in the oral cavity are given in this review. How frequently this occurs in dental plaque is not clear, but evidence suggests that it a...

  19. Denitrification in human dental plaque

    OpenAIRE

    Verstraete Willy; Heisterkamp Ines M; Gieseke Armin; Stief Peter; Schreiber Frank; de Beer Dirk; Stoodley Paul

    2010-01-01

    Abstract Background Microbial denitrification is not considered important in human-associated microbial communities. Accordingly, metabolic investigations of the microbial biofilm communities of human dental plaque have focused on aerobic respiration and acid fermentation of carbohydrates, even though it is known that the oral habitat is constantly exposed to nitrate (NO3-) concentrations in the millimolar range and that dental plaque houses bacteria that can reduce this NO3- to nitrite (NO2-...

  20. Overexpression of amyloid precursor protein inhibits neurite outgrowth and disrupts cytoskeleton in N2a cells

    Institute of Scientific and Technical Information of China (English)

    王泽芬; 王建枝

    2004-01-01

    @@ There is considerable evidence suggesting that altered metabolism of β-amyloid precursor protein (APP) and accumulation of its β-amyloid (Aβ) fragment are key features of Alzheimer's disease (AD). APP is a type Ⅰ integral membrane protein and consists of 695-770 amino acids encoded by differentially spliced mRNAs transcribed from a single gene located on human chromosome 21.1 The 695-amino acid APP is expressed preferentially in the brain. Aβ, the major component of senile plaques, is derived by proteolytic processing of APP by β-and γ-secretase and is constitutively released from most cells.

  1. Human Islet Amyloid Polypeptide

    DEFF Research Database (Denmark)

    Kosicka, Iga

    2014-01-01

    Diabetes mellitus type II is a metabolic disease affecting millions of people worldwide. The disease is associated with occurence of insoluble, fibrillar, protein aggregates in islets of Langerhans in the pancreas - islet amyloid. The main constituent of these protein fibers is the human islet...

  2. 淀粉样β-蛋白在阿尔茨海默病突触可塑性中的作用%Role of β-amyloid Protein in Synaptic Plasticity of Alzheimer’ s Disease

    Institute of Scientific and Technical Information of China (English)

    张锦辉; 郑琳琳

    2014-01-01

    Alzheimer ’ s disease ( AD) is a common type of dementia .Though it is closely related to age , its exact pathogenesis has still been unclear .Senile plaques will appear in the brain of the patient attacked by AD and the core component of the plaques is amyloid β-protein ( Aβ) .Aβdepositions abnormally in the brain may de-crease the synaptic plasticity and affect the hippocampal long -term potentiation .Studies have shown that the main component of Aβthat has neurotoxic effects is oligomers such as Aβ1-40 and Aβ1-42 etc.they can inactivate N-methyl-D-aspartate ( NMDA) receptor and abnormally increase the glutamate in brain mediated by NMDA re-ceptor , and finally reduce the learning and memory ability of the patient .%阿尔茨海默病是老年痴呆的常见类型,与年龄密切相关,目前AD的确切发病机制仍不十分清楚。 AD发生后脑内出现老年斑,其核心成分为淀粉样β-蛋白( amyloid β-peptide , Aβ)。 Aβ在脑内的异常沉积导致突触可塑性降低,影响海马长时程增强过程。研究表明Aβ发挥神经毒性作用主要是其寡聚体,如Aβ1-40和Aβ1-42等,使N-甲基-D-天冬氨酸( NMDA)的受体失活,导致NMDA受体介导的谷氨酸异常增高,最终体现为学习记忆能力下降。

  3. DBA/2J Genetic Background Exacerbates Spontaneous Lethal Seizures but Lessens Amyloid Deposition in a Mouse Model of Alzheimer’s Disease

    OpenAIRE

    Jackson, Harriet M.; Onos, Kristen D.; Pepper, Keating W.; Graham, Leah C; Akeson, Ellen C.; Byers, Candice; Reinholdt, Laura G; Frankel, Wayne N.; Howell, Gareth R.

    2015-01-01

    Alzheimer’s disease (AD) is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs) and neuronal dysfunction. Early onset AD (EOAD) is commonly caused by mutations in amyloid precursor protein (APP) or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2). In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but sig...

  4. Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of Amyloid-β in Th1- and Th17-Versions of Experimental Autoimmune Encephalomyelitis

    OpenAIRE

    Grant, Jacqueline L.; Ghosn, Eliver Eid Bou; Axtell, Robert C.; Herges, Katja; Kuipers, Hedwich F.; Woodling, Nathan S.; Andreasson, Katrin; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Steinman, Lawrence

    2012-01-01

    β-amyloid-42 (Aβ42) and β-amyloid-40 (Aβ40), major components of senile plaque deposits in Alzheimer’s disease (AD), are considered neurotoxic and pro-inflammatory. In multiple sclerosis (MS), Aβ42 is upregulated in brain lesions and damaged axons. Here we found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction ...

  5. A potential amyloid-imaging probe for Alzheimer's disease

    International Nuclear Information System (INIS)

    Purpose: To screen out the human single-chain fragment variable (scFv) against amyloid β peptide 40 from a human synthetic antibody library, sub-clone its gene into E. coli expression system, and express and purify it for amyloid peptide imaging research. The overload of amyloid β peptide and the appearance of senile plaques in the human brain tissue is one of the hallmark of the Alzheimer's disease, and in vivo imaging of amyloidβ peptide is valuable for the earlier diagnosis of Alzheimer's disease. Methods: Amyloid β peptide 40 was bound on the solid surface of Nunc plates as antigen and a human antibody library constructed with human antibody heavy and light chain variable gene and nucleotides sequence coded (Gly4Ser)3 linker and displayed on the protein surface of filamentous phage was used to screen the binding clones. After five rounds of bio-panning, the host E. coli TG1 was infected with eluted filamentous phage from the last turn of selection. 55 well-separated colonies were picked randomly from the plates and several specific positive clones were identified by ELISA testing, and their binding sites were determined by competitive ELISA with amyloid 13 peptide 40, 1-16, 25-35. The single-chain Fv antibody gene was sequenced and their amino acids sequence was deduced. The scFv antibody gene was sub-cloned into a protokayotic expression vector pET-22b(+) and transformed into bacteria strain BL21 to express the His6-tagged single-chain antibody and the whole cell culture was subjected to SDS-PAGE analysis. The antibody was expressed in inclusion bodies and purified with serial buffers and verified with western blotting and their activity was tested by ELISA against amyloid β peptide 40. Results: ELISA testing showed that 33 clones could bind amyloid β peptide 40 and 10 of these clones could be inhibited by amyloid β peptide 40 itself to below 50% of its original binding activities. Five clones could also be inhibited by amyloid β peptide 1-16. DNA

  6. Amyloids here, amyloids there…What’s wrong with them?

    OpenAIRE

    Gharibyan, Anna

    2012-01-01

    Amyloid formation is inherent property of proteins which under certain circumstances can become a pathologic feature of a group of diseases called amyloidosis. There are about 30 known human amyloidosis and more than 27 identified proteins involved in these pathologies.  Besides these proteins, there are a growing number of proteins non-related to diseases shown to form amyloid-like structures in vitro, which make them excellent tools for studying amyloid formation mechanisms, physicochemical...

  7. Beta-secretase-cleaved amyloid precursor protein in Alzheimer brain: a morphologic study

    DEFF Research Database (Denmark)

    Sennvik, Kristina; Bogdanovic, N; Volkmann, Inga; Fastbom, J; Benedikz, Eirikur

    2004-01-01

    (beta-sAPP) in brain tissue sections from the frontal, temporal and occipital lobe. Strong granular beta-sAPP staining was found throughout the gray matter of all three areas, while white matter staining was considerably weaker. beta-sAPP was found to be localized in astrocytes and in axons. We found...... the beta-sAPP immunostaining to be stronger and more extensive in gray matter in Alzheimer disease (AD) cases than controls. The axonal beta-sAPP staining was patchy and unevenly distributed for the AD cases, indicating impaired axonal transport. beta-sAPP was also found surrounding senile plaques and......beta-amyloid (Abeta) is the main constituent of senile plaques seen in Alzheimer's disease. Abeta is derived from the amyloid precursor protein (APP) via proteolytic cleavage by proteases beta- and gamma-secretase. In this study, we examined content and localization of beta-secretase-cleaved APP...

  8. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain

    OpenAIRE

    Cox, Paul Alan; Davis, David A.; Mash, Deborah C.; Metcalf, James S.; Banack, Sandra Anne

    2016-01-01

    Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments...

  9. Beta-amyloid peptide blocks the fast-inactivating K+ current in rat hippocampal neurons.

    OpenAIRE

    Good, T A; Smith, D. O.; Murphy, R M

    1996-01-01

    Deposition of beta-amyloid peptide (A beta) in senile plaques is a hallmark of Alzheimer disease neuropathology. Chronic exposure of neuronal cultures to synthetic A beta is directly toxic, or enhances neuronal susceptibility to excitotoxins. Exposure to A beta may cause a loss of cellular calcium homeostasis, but the mechanism by which this occurs is uncertain. In this work, the acute response of rat hippocampal neurons to applications of synthetic A beta was measured using whole-cell voltag...

  10. Mathematical modeling for the pathogenesis of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Ishwar K Puri

    Full Text Available Despite extensive research, the pathogenesis of neurodegenerative Alzheimer's disease (AD still eludes our comprehension. This is largely due to complex and dynamic cross-talks that occur among multiple cell types throughout the aging process. We present a mathematical model that helps define critical components of AD pathogenesis based on differential rate equations that represent the known cross-talks involving microglia, astroglia, neurons, and amyloid-β (Aβ. We demonstrate that the inflammatory activation of microglia serves as a key node for progressive neurodegeneration. Our analysis reveals that targeting microglia may hold potential promise in the prevention and treatment of AD.

  11. In vivo labeling of amyloid with BF-108.

    Science.gov (United States)

    Suemoto, Takahiro; Okamura, Nobuyuki; Shiomitsu, Tsuyoshi; Suzuki, Masako; Shimadzu, Hiroshi; Akatsu, Hiroyasu; Yamamoto, Takayuki; Kudo, Yukitsuka; Sawada, Tohru

    2004-01-01

    Detection of aggregated amyloid-beta (Abeta) with a non-invasive imaging modality such as positron emission tomography (PET) was suggested to be ideal for the diagnosis of Alzheimer's disease (AD) prior to the onset of clinical symptoms. We have been searching for imaging probe candidates with a high affinity for aggregated Abeta in vitro and in vivo and high lipophilicity, a characteristic that allows for the permeation of the blood-brain barrier (BBB). As analyzed by Thioflavin T (ThT) assay and octanol/water partition coefficient test (PC), 3-diethylamino-6-(2-fluoroethyl)ethylaminoacridine (BF-108) were found to have high affinity for Abeta aggregates in vitro and high lipophilicity. Intravenously administrated BF-108 labeled Abeta aggregates injected into the amygdala as observed under a fluorescence microscope, showing this compound's permeability of BBB and an ability to label Abeta in vivo. BF-108 also labeled neuritic senile plaques (SPs), neurofibrillary tangles, and amyloid-laden vessels in temporal and hippocampal sections from AD patients. Following intravenous administration of BF-108 to an APP23 transgenic (TG) mouse, in vivo labeling of endogenous plaques was seen in brain sections by fluorescence microscopy. These properties suggest the potential utility of BF-108 for in vivo imaging of AD pathology. PMID:14687882

  12. 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.

  13. Musculoskeletal amyloid disease: MRI features

    International Nuclear Information System (INIS)

    A case of arthropathy and soft tissue masses due to amyloid deposition in a patient with myeloma is reported. The radiologic and magnetic resonance findings of musculoskeletal amyloidosis are described. The amyloid masses show heterogeneous signal intensity, with a signal lower than muscle and intermingled areas of marked hyperintensity on T 2-weighted images. (authors). 7 refs., 2 figs

  14. Musculoskeletal amyloid disease: MRI features

    Energy Technology Data Exchange (ETDEWEB)

    Del Castillo, M.; Guerra, J.L. [Hospital Arquitecto Marcide, Ferrol (Spain); Comesana, L.; Martin, R. [Hospital Arquitecto Marcide, Ferrol (Spain)]|[Hospital Juan Canalejo, La Coruna (Spain); Rodriguez, E.; Soler, R. [Hospital Juan Canalejo, La Coruna (Spain)

    1995-12-31

    A case of arthropathy and soft tissue masses due to amyloid deposition in a patient with myeloma is reported. The radiologic and magnetic resonance findings of musculoskeletal amyloidosis are described. The amyloid masses show heterogeneous signal intensity, with a signal lower than muscle and intermingled areas of marked hyperintensity on T 2-weighted images. (authors). 7 refs., 2 figs.

  15. Nuclear Molecular Imaging for Vulnerable Atherosclerotic Plaques

    OpenAIRE

    Lee, Soo Jin; Paeng, Jin Chul

    2015-01-01

    Atherosclerosis is an inflammatory disease as well as a lipid disorder. Atherosclerotic plaque formed in vessel walls may cause ischemia, and the rupture of vulnerable plaque may result in fatal events, like myocardial infarction or stroke. Because morphological imaging has limitations in diagnosing vulnerable plaque, molecular imaging has been developed, in particular, the use of nuclear imaging probes. Molecular imaging targets various aspects of vulnerable plaque, such as inflammatory cell...

  16. Ultrasound Tissue Characterization of Vulnerable Atherosclerotic Plaque

    Directory of Open Access Journals (Sweden)

    Eugenio Picano

    2015-05-01

    Full Text Available A thrombotic occlusion of the vessel fed by ruptured coronary atherosclerotic plaque may result in unstable angina, myocardial infarction or death, whereas embolization from a plaque in carotid arteries may result in transient ischemic attack or stroke. The atherosclerotic plaque prone to such clinical events is termed high-risk or vulnerable plaque, and its identification in humans before it becomes symptomatic has been elusive to date. Ultrasonic tissue characterization of the atherosclerotic plaque is possible with different techniques—such as vascular, transesophageal, and intravascular ultrasound—on a variety of arterial segments, including carotid, aorta, and coronary districts. The image analysis can be based on visual, video-densitometric or radiofrequency methods and identifies three distinct textural patterns: hypo-echoic (corresponding to lipid- and hemorrhage-rich plaque, iso- or moderately hyper-echoic (fibrotic or fibro-fatty plaque, and markedly hyperechoic with shadowing (calcific plaque. Hypoechoic or dishomogeneous plaques, with spotty microcalcification and large plaque burden, with plaque neovascularization and surface irregularities by contrast-enhanced ultrasound, are more prone to clinical complications than hyperechoic, extensively calcified, homogeneous plaques with limited plaque burden, smooth luminal plaque surface and absence of neovascularization. Plaque ultrasound morphology is important, along with plaque geometry, in determining the atherosclerotic prognostic burden in the individual patient. New quantitative methods beyond backscatter (to include speed of sound, attenuation, strain, temperature, and high order statistics are under development to evaluate vascular tissues. Although not yet ready for widespread clinical use, tissue characterization is listed by the American Society of Echocardiography roadmap to 2020 as one of the most promising fields of application in cardiovascular ultrasound imaging

  17. Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.

    Directory of Open Access Journals (Sweden)

    Yan Zheng

    Full Text Available Alzheimer's disease (AD is the most common progressive neurodegenerative disease known to humankind. It is characterized by brain atrophy, extracellular amyloid plaques, and intracellular neurofibril tangles. β-Amyloid cascade is considered the major causative player in AD. Up until now, the mechanisms underlying the process of Aβ generation and accumulation in the brain have not been well understood. Tyro3 receptor belongs to the TAM receptor subfamily of receptor protein tyrosine kinases (RPTKs. It is specifically expressed in the neurons of the neocortex and hippocampus. In this study, we established a cell model stably expressing APPswe mutants and producing Aβ. We found that overexpression of Tyro3 receptor in the cell model significantly decreased Aβ generation and also down-regulated the expression of β-site amyloid precursor protein cleaving enzyme (BACE1. However, the effects of Tyro3 were inhibited by its natural ligand, Gas6, in a concentration-dependent manner. In order to confirm the role of Tyro3 in the progression of AD development, we generated an AD transgenic mouse model accompanied by Tyro3 knockdown. We observed a significant increase in the number of amyloid plaques in the hippocampus in the mouse model. More plaque-associated clusters of astroglia were also detected. The present study may help researchers determine the role of Tyro3 receptor in the neuropathology of AD.

  18. Chlamydia pneumoniae in atherosclerotic carotid artery plaques: high prevalence among heavy smokers.

    Science.gov (United States)

    Dobrilovic, N; Vadlamani, L; Meyer, M; Wright, C B

    2001-06-01

    This study was designed to determine the prevalence of Chlamydia pneumoniae in carotid artery plaques. Although there have been numerous studies evaluating coronary plaques for this bacterium fewer studies have assessed noncoronary vasculature. In addition we wished to evaluate whether correlation exists between the presence of C. pneumoniae in carotid plaques and established risk factors for atherosclerosis. Sixty intact carotid artery plaques removed during surgery (carotid endarterectomy) were formalin-fixed and paraffin-embedded according to conventional techniques. These samples were evaluated by polymerase chain reaction analysis to detect presence of C. pneumoniae DNA. Results were tabulated and compared against established risk factors for atherosclerosis: diabetes, hypertension, hyperlipidemia, age, and smoking. Forty-two (70.0%) of the 60 plaques that were evaluated tested positive for the presence of C. pneumoniae DNA by polymerase chain reaction analysis. In the sample defined as being from heavy smokers (greater than 15-pack-year history) 33 (94.3%) of 35 plaques tested positive whereas two (5.7%) tested negative. This correlation demonstrated statistical significance (P = 1.36 x 10(-6), two-tailed Fisher exact test). Presence of C. pneumoniae in carotid plaques demonstrated no statistically significant correlation with diabetes, hypertension, or hyperlipidemia. Age as a risk factor was examined but not statistically evaluated because of the narrow range within our patient sample. Analysis of the data reveals that C. pneumoniae is present in large numbers of atheromatous plaques as is consistent with emerging data. What is interesting though is that 33 (94.3%) of the 35 smokers had plaques that tested positive for the bacterium as opposed to only nine (36.0%) of the 25 nonsmokers. Identification of specific populations exhibiting a high prevalence of C. pneumoniae may serve to focus future studies. Ongoing investigation will seek to determine whether C

  19. Cholesterol Depletion Reduces the Internalization of β-Amyloid Peptide in SH-SY5Y Cells

    Institute of Scientific and Technical Information of China (English)

    ZHOU Qinghua; HE Li; SUI Senfang

    2006-01-01

    Deposition of amyloid in the brain is a critical step in the pathogenesis of Alzheimer's disease. The endocytosis of β-amyloid peptide (Aβ) is an important factor among the many factors that contribute to the genesis of amyloid deposits. Since cholesterol participates in many important physiological processes, the present work investigated the relationship between the cellular cholesterol content and the endocytosis of the exogenic Aβ, and found that reduction of the cholesterol content by methyl-β-cyclodextrin could reduce the endocytosis of Aβ. The study indicates that the endocytosis of Aβ is partly mediated by cholesterol.

  20. Increased efflux of amyloid-β peptides through the blood-brain barrier by muscarinic acetylcholine receptor inhibition reduces pathological phenotypes in mouse models of brain amyloidosis.

    Science.gov (United States)

    Paganetti, Paolo; Antoniello, Katia; Devraj, Kavi; Toni, Nicolas; Kieran, Dairin; Madani, Rime; Pihlgren, Maria; Adolfsson, Oskar; Froestl, Wolfgang; Schrattenholz, André; Liebner, Stefan; Havas, Daniel; Windisch, Manfred; Cirrito, John R; Pfeifer, Andrea; Muhs, Andreas

    2014-01-01

    The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL, and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Brain (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. PMID:24072071

  1. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    Energy Technology Data Exchange (ETDEWEB)

    Dhanjal, Jaspreet Kaur [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India); Goyal, Sukriti [Apaji Institute of Mathematics and Applied Computer Technology, Banasthali University, Tonk 304022, Rajasthan (India); Sharma, Sudhanshu [Department of Biotechnology, Delhi Technological University, New Delhi 110042 (India); Hamid, Rabia [Department of Biochemistry, University of Kashmir, Srinagar 190006 (India); Grover, Abhinav, E-mail: abhinavgr@gmail.com [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India)

    2014-01-17

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease.

  2. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    International Nuclear Information System (INIS)

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease

  3. Magnetite-Amyloid-β deteriorates activity and functional organization in an in vitro model for Alzheimer’s disease

    Science.gov (United States)

    Teller, Sara; Tahirbegi, Islam Bogachan; Mir, Mònica; Samitier, Josep; Soriano, Jordi

    2015-11-01

    The understanding of the key mechanisms behind human brain deterioration in Alzheimer’ disease (AD) is a highly active field of research. The most widespread hypothesis considers a cascade of events initiated by amyloid-β peptide fibrils that ultimately lead to the formation of the lethal amyloid plaques. Recent studies have shown that other agents, in particular magnetite, can also play a pivotal role. To shed light on the action of magnetite and amyloid-β in the deterioration of neuronal circuits, we investigated their capacity to alter spontaneous activity patterns in cultured neuronal networks. Using a versatile experimental platform that allows the parallel monitoring of several cultures, the activity in controls was compared with the one in cultures dosed with magnetite, amyloid-β and magnetite-amyloid-β complex. A prominent degradation in spontaneous activity was observed solely when amyloid-β and magnetite acted together. Our work suggests that magnetite nanoparticles have a more prominent role in AD than previously thought, and may bring new insights in the understanding of the damaging action of magnetite-amyloid-β complex. Our experimental system also offers new interesting perspectives to explore key biochemical players in neurological disorders through a controlled, model system manner.

  4. Serum Amyloid A as a Marker of Persistent Inflammation and an Indicator of Cardiovascular and Renal Involvement in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Bożena Targońska-Stępniak

    2014-01-01

    Full Text Available Objectives. Rheumatoid arthritis (RA is a systemic, inflammatory disease. Serum amyloid A (SAA is an acute-phase protein, involved in pathogenesis of atherosclerosis. The aim of the study was to assess serum concentration of SAA in RA patients, with reference to other inflammatory parameters and markers of extra-articular involvement. Methods. The study population consisted of 140 RA patients, low/moderate disease activity (L/MDA in 98 (70% patients and high disease activity (HDA in 42 (30%. Comprehensive clinical and laboratory assessment was performed with evaluation of electrocardiogram and carotid intima-media thickness. Results. The mean SAA concentration [327.0 (263.4 mg/L] was increased highly above the normal value, even in patients with L/MDA. Simultaneously, SAA was significantly higher in patients with HDA versus L/MDA. The mean SAA concentration was significantly higher in patients treated with glucocorticoids, was inversely associated with QTc duration, and was markedly higher in patients with atherosclerotic plaques, emphasizing increased CV risk. SAA was significantly higher in patients with increased cystatin-C level. Conclusions. In RA patients, high serum SAA concentration was strongly associated with activity of the disease and risk of CV and renal involvement. Recurrent assessment of SAA may facilitate searching patients with persistent inflammation and risk of extra-articular complications.

  5. The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer’s Disease

    OpenAIRE

    Gholamreza Azizi; Navabi, Shadi S.; Ahmed Al-Shukaili; Mir H. Seyedzadeh; Reza Yazdani; Abbas Mirshafiey

    2015-01-01

    Alzheimer’s disease (AD), a neurodegenerative disorder associated with advanced age, is the most common cause of dementia globally. AD is characterised by cognitive dysfunction, deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Inflammation of the brain is a key pathological hallmark of AD. Thus, clinical and immunopathological evidence of AD could be potentially supported by inflammatory mediators, including cytokines, chemokines, the complement system, acute pha...

  6. Inflammation and Atherosclerosis: Current Pathogenesis

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2012-08-01

    Full Text Available BACKGROUND: The inflammatory nature of atherosclerosis is well established but the agent(s that incite inflammation in the artery wall remain largely unknown. CONTENT: Chronic inflammation is recognized as a major driving force in atherogenesis. The sites of atherosclerotic plaque development in the arterial wall are characterized by cholesterol accumulation and infiltration of peripheral blood monocytes, which gradually differentiate into macrophages. Cholesterol crystals, the common constituents of atherosclerotic lesions, include NLRP3 inflammasome activation and IL-1β secretion in human macrophages, promote an inflammatory milieu and thus drive lesion progression. Consequently, the cholesterol crystal-induced inflammasome activation may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions. SUMMARY: The crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions. This finding provides new insights into the pathogenesis of atherosclerosis and indicates new potential molecular targets for the therapy of this disease. KEYWORDS: atherosclerosis, inflammation, neutrophil, macrophages, inflammasome, cholesterol crystal.

  7. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Adriaanse, Sofie M. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Amsterdam (Netherlands); VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, P.O. Box 7057, Amsterdam (Netherlands); Van Dijk, Koene R.A. [Harvard University, Department of Psychology, Center for Brain Science, Cambridge, MA (United States); Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Ossenkoppele, Rik; Tolboom, Nelleke; Zwan, Marissa D.; Barkhof, Frederik; Berckel, Bart N.M. van [VU University Medical Center, Department of Radiology and Nuclear Medicine, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Reuter, Martin [Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA (United States); Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Laboratory, Division of Health Sciences and Technology, Cambridge, MA (United States); Yaqub, Maqsood; Boellaard, Ronald; Windhorst, Albert D.; Lammertsma, Adriaan A. [VU University Medical Center, Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, Amsterdam (Netherlands); Flier, Wiesje M. van der; Scheltens, Philip [VU University Medical Center, Department of Neurology, Alzheimer Center, Neuroscience Campus Amsterdam, Amsterdam (Netherlands)

    2014-06-15

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [{sup 11}C]PIB to assess amyloidplaque load and [{sup 18}F]FDG to assess glucose metabolism. [{sup 11}C]PIB binding and [{sup 18}F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloidplaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p < 0.05). The present study shows that in a group of AD patients amyloidplaque load as measured by [{sup 11}C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [{sup 18}F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  8. The effect of amyloid pathology and glucose metabolism on cortical volume loss over time in Alzheimer's disease

    International Nuclear Information System (INIS)

    The present multimodal neuroimaging study examined whether amyloid pathology and glucose metabolism are related to cortical volume loss over time in Alzheimer's disease (AD) patients and healthy elderly controls. Structural MRI scans of eleven AD patients and ten controls were available at baseline and follow-up (mean interval 2.5 years). Change in brain structure over time was defined as percent change of cortical volume within seven a-priori defined regions that typically show the strongest structural loss in AD. In addition, two PET scans were performed at baseline: [11C]PIB to assess amyloidplaque load and [18F]FDG to assess glucose metabolism. [11C]PIB binding and [18F]FDG uptake were measured in the precuneus, a region in which both amyloid deposition and glucose hypometabolism occur early in the course of AD. While amyloidplaque load at baseline was not related to cortical volume loss over time in either group, glucose metabolism within the group of AD patients was significantly related to volume loss over time (rho = 0.56, p 11C]PIB behaves as a trait marker (i.e., all AD patients showed elevated levels of amyloid, not related to subsequent disease course), whilst hypometabolism as measured by [18F]FDG changed over time indicating that it could serve as a state marker that is predictive of neurodegeneration. (orig.)

  9. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation

    International Nuclear Information System (INIS)

    Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome. (orig.)

  10. Close association of arterial plaques with left ventricular hypertrophy and ejection fraction in hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Mowlaie Morteza

    2014-01-01

    Full Text Available Introduction: In renal failure patients, cardiovascular complications are a major clinical problem. Objectives: This study aimed to test, the possible association of left ventricular hypertrophy and ejection fraction with plaques of carotid and femoral artery hemodialysis. Patients and Methods: Sixty-one patients, who were on regular hemodialysis were selected. For all patients echocardiography and B-mode Ultrsonographic assessment of carotid-femoral arteries for plaque occurrence were conducted. Results: In this study there was a positive correlation between left ventricular hypertrophy with the duration of hemodialysis treatment (p<0.05. Significant positive association between left ventricular hypertrophy and plaque score and also a significant positive association between left ventricular hypertrophy with presence of chest pain was found (p<0.05. Association of diabetes mellitus with the presence of chest pain was positive. Positive correlation between hypertension with plaque score was demonstrated too (p<0.05. Also an inverse association of plaque score with left ventricular ejection fraction was detected too (p<0.05. Furthermore, the correlation of plaque score with the presence of diabetes mellitus was positive. Conclusion: The present investigations, documents parallel cardiac and vascular adaptation in hemodialysis patients and shows the potential contribution of structural and functional large artery alteration to the pathogenesis of left ventricular hypertrophy which needs more attention in patients on hemodialysis.

  11. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer’s disease

    Science.gov (United States)

    Saint-Aubert, Laure; Carter, Stephen F.; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-01-01

    See Schott and Fox (doi:10.1093/brain/awv405) for a scientific commentary on this article. Alzheimer’s disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer’s disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer 11C-deuterium-L-deprenyl), fibrillar amyloidplaque deposition (11C-Pittsburgh compound B), and glucose metabolism (18F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer’s disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer’s disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer’s disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into 11C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and 11C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants

  12. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    See Schott and Fox (doi:10.1093/brain/awv405) for a scientific commentary on this article.Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloidplaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants

  13. Bilateral Auricular Milia en Plaque

    Directory of Open Access Journals (Sweden)

    Savaş

    2011-12-01

    Full Text Available Milia en plaque (MEP is an extremely rare form of milia that is characterized by a number of milia-like cysts on an erythematous base and histologically exhibits features of keratin cysts. The etiology is not exactly known. MEP is generally seen among middle-aged women and especially on the head and neck region. Many of the diagnosed cases are localized in the retroauricular region, eyelids and the nose region. To date, no case of MEP in the auricula has been reported in the literature. In this article, we present the case of a 71-year-old female patient clinically and histologically diagnosed with bilateral auricular milia en plaque (in the external ear canal in the light of current literature. (Turk­derm 2011; 45: 216-8

  14. Tritium-labeled (E,E)-2,5-bis(4'-hydroxy-3'-carboxystyryl)benzene as a probe for β-amyloid fibrils.

    Science.gov (United States)

    Matveev, Sergey V; Kwiatkowski, Stefan; Sviripa, Vitaliy M; Fazio, Robert C; Watt, David S; LeVine, Harry

    2014-12-01

    Accumulation of Aβ in the brains of Alzheimer disease (AD) patients reflects an imbalance between Aβ production and clearance from their brains. Alternative cleavage of amyloid precursor protein (APP) by processing proteases generates soluble APP fragments including the neurotoxic amyloid Aβ40 and Aβ42 peptides that assemble into fibrils and form plaques. Plaque-buildup occurs over an extended time-frame, and the early detection and modulation of plaque formation are areas of active research. Radiolabeled probes for the detection of amyloid plaques and fibrils in living subjects are important for noninvasive evaluation of AD diagnosis, progression, and differentiation of AD from other neurodegenerative diseases and age-related cognitive decline. Tritium-labeled (E,E)-1-[(3)H]-2,5-bis(4'-hydroxy-3'-carbomethoxystyryl)benzene possesses an improved level of chemical stability relative to a previously reported radioiodinated analog for radiometric quantification of Aβ plaque and tau pathology in brain tissue and in vitro studies with synthetic Aβ and tau fibrils. PMID:25452000

  15. Dynamics of mussel plaque detachment

    OpenAIRE

    Desmond, KW; Zacchia, NA; Waite, JH; Valentine, MT

    2015-01-01

    © The Royal Society of Chemistry 2015. Mussels are well known for their ability to generate and maintain strong, long-lasting adhesive bonds under hostile conditions. Many prior studies attribute their adhesive strength to the strong chemical interactions between the holdfast and substrate. While chemical interactions are certainly important, adhesive performance is also determined by contact geometry, and understanding the coupling between chemical interactions and the plaque shape and mecha...

  16. Stickland reactions of dental plaque.

    OpenAIRE

    Curtis, M A; Kemp, C W; Robrish, S A; Bowen, W H

    1983-01-01

    Dental plaque samples from monkeys (Macaca fascicularis) were shown to contain proline reduction activity in coupled Stickland reactions with other amino acids and also with certain end products of bacterial glucose metabolism. The unusually high concentration of bound and free proline in the oral environment may be of importance in both the production of base and in the removal of acid from the tooth surface after dietary carbohydrate ingestion.

  17. Bacterial sex in dental plaque

    Directory of Open Access Journals (Sweden)

    Ingar Olsen

    2013-06-01

    Full Text Available Genes are transferred between bacteria in dental plaque by transduction, conjugation, and transformation. Membrane vesicles can also provide a mechanism for horizontal gene transfer. DNA transfer is considered bacterial sex, but the transfer is not parallel to processes that we associate with sex in higher organisms. Several examples of bacterial gene transfer in the oral cavity are given in this review. How frequently this occurs in dental plaque is not clear, but evidence suggests that it affects a number of the major genera present. It has been estimated that new sequences in genomes established through horizontal gene transfer can constitute up to 30% of bacterial genomes. Gene transfer can be both inter- and intrageneric, and it can also affect transient organisms. The transferred DNA can be integrated or recombined in the recipient's chromosome or remain as an extrachromosomal inheritable element. This can make dental plaque a reservoir for antimicrobial resistance genes. The ability to transfer DNA is important for bacteria, making them better adapted to the harsh environment of the human mouth, and promoting their survival, virulence, and pathogenicity.

  18. Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease

    DEFF Research Database (Denmark)

    Baron, Rona; Babcock, Alicia A; Nemirovsky, Anna;

    2014-01-01

    earlier in mouse models of Alzheimer's disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with...... a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to...

  19. Interactions of laminin with the amyloid ß peptide: Implications for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Morgan C.

    2001-01-01

    Full Text Available Extensive neuronal cell loss is observed in Alzheimer's disease. Laminin immunoreactivity colocalizes with senile plaques, the characteristic extracellular histopathological lesions of Alzheimer brain, which consist of the amyloid ß (Aß peptide polymerized into amyloid fibrils. These lesions have neurotoxic effects and have been proposed to be a main cause of neurodegeneration. In order to understand the pathological significance of the interaction between laminin and amyloid, we investigated the effect of laminin on amyloid structure and toxicity. We found that laminin interacts with the Aß1-40 peptide, blocking fibril formation and even inducing depolymerization of preformed fibrils. Protofilaments known to be intermediate species of Aß fibril formation were also detected as intermediate species of laminin-induced Aß fibril depolymerization. Moreover, laminin-amyloid interactions inhibited the toxic effects on rat primary hippocampal neurons. As a whole, our results indicate a putative anti-amyloidogenic role of laminin which may be of biological and therapeutic interest for controlling amyloidosis, such as those observed in cerebral angiopathy and Alzheimer's disease.

  20. A chemical analog of curcumin as an improved inhibitor of amyloid Abeta oligomerization.

    Directory of Open Access Journals (Sweden)

    Robert A Orlando

    Full Text Available Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD. The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved

  1. Multimodality Intravascular Imaging Assessment of Plaque Erosion versus Plaque Rupture in Patients with Acute Coronary Syndrome

    Science.gov (United States)

    Kwon, Jee Eun; Mintz, Gary S.; Hong, Young Joon; Lee, Sung Yun; Kim, Ki Seok; Hahn, Joo-Yong; Kumar, Kaup Sharath; Won, Hoyoun; Hyeon, Seong Hyeop; Shin, Seung Yong; Lee, Kwang Je; Kim, Tae Ho; Kim, Chee Jeong; Kim, Sang Wook

    2016-01-01

    Background and Objectives We assessed plaque erosion of culprit lesions in patients with acute coronary syndrome in real world practice. Subjects and Methods Culprit lesion plaque rupture or plaque erosion was diagnosed with optical coherence tomography (OCT). Intravascular ultrasound (IVUS) was used to determine arterial remodeling. Positive remodeling was defined as a remodeling index (lesion/reference EEM [external elastic membrane area) >1.05. Results A total of 90 patients who had plaque rupture showing fibrous-cap discontinuity and ruptured cavity were enrolled. 36 patients showed definite OCT-plaque erosion, while 7 patients had probable OCT-plaque erosion. Overall, 26% (11/43) of definite/probable plaque erosion had non-ST elevation myocardial infarction (NSTEMI) while 35% (15/43) had ST elevation myocardial infarction (STEMI). Conversely, 14.5% (13/90) of plaque rupture had NSTEMI while 71% (64/90) had STEMI (p<0.0001). Among plaque erosion, white thrombus was seen in 55.8% (24/43) of patients and red thrombus in 27.9% (12/43) of patients. Compared to plaque erosion, plaque rupture more often showed positive remodeling (p=0.003) with a larger necrotic core area examined by virtual histology (VH)-IVUS, while negative remodeling was prominent in plaque erosion. Overall, 65% 28/43 of plaque erosions were located in the proximal 30 mm of a culprit vessel-similar to plaque ruptures (72%, 65/90, p=0.29). Conclusion Although most of plaque erosions show nearly normal coronary angiogram, modest plaque burden with negative remodeling and an uncommon fibroatheroma might be the nature of plaque erosion. Multimodality intravascular imaging with OCT and VH-IVUS showed fundamentally different pathoanatomic substrates underlying plaque rupture and erosion. PMID:27482258

  2. A cytotoxic amyloid oligomer self-triggered and NIR- enhanced amyloidosis therapeutic system

    Institute of Scientific and Technical Information of China (English)

    Can Xu[1,2; Peng Shi[1,2; Meng Li[1,2; Jinsong Ren[1; xiaogang Qu[1

    2015-01-01

    We report a new strategy for improving the efficiency of non-specific amyloidosis therapeutic drugs by coating amyloid-responsive lipid bilayers. The approach had drawn inspiration from amyloid oligomer-mediated cell membrane disruption in the pathogenesis of amyloidosis. A graphene-mesoporous silica hybrid (GMS)-supported lipid bilayer (GMS-Lip) system was used as a drug carrier, Drugs were well confined inside the nanocarrier until encountering amyloid oligomers, which could pierce the lipid bilayer coat and cause drug release. To ensure release efficiency, use of a near-infrared (NIR) laser was also introduced to facilitate drug release, taking advantage of the photothermal effect of GMS and thermal sensitivity of lipid bilayers. To facilitate tracking, fluorescent dyes were co-loaded with drugs within GMS-Lip and the NIR laser was used once the oligomer-triggered release had been signaled. Because of the spatially and temporally controllable property of light, the NIR-assisted release could be easily and selectively activated locally by tracking the fluorescence signal. Our design is based on arnyloidosis pathogenesis, the cytotoxic amyloid oligomer self-triggered release via cell membrane disruption, for the controlled release of drug molecules. The results may shed light on the development of pathogenesis- inspired drug delivery systems,

  3. ATP-binding cassette transporter A7 (ABCA7) loss of function alters Alzheimer amyloid processing.

    Science.gov (United States)

    Satoh, Kanayo; Abe-Dohmae, Sumiko; Yokoyama, Shinji; St George-Hyslop, Peter; Fraser, Paul E

    2015-10-01

    The ATP-binding cassette transporter A7 (ABCA7) has been identified as a susceptibility factor of late onset Alzheimer disease in genome-wide association studies. ABCA7 has been shown to mediate phagocytosis and affect membrane trafficking. The current study examined the impact of ABCA7 loss of function on amyloid precursor protein (APP) processing and generation of amyloid-β (Aβ). Suppression of endogenous ABCA7 in several different cell lines resulted in increased β-secretase cleavage and elevated Aβ. ABCA7 knock-out mice displayed an increased production of endogenous murine amyloid Aβ42 species. Crossing ABCA7-deficient animals to an APP transgenic model resulted in significant increases in the soluble Aβ as compared with mice expressing normal levels of ABCA7. Only modest changes in the amount of insoluble Aβ and amyloid plaque densities were observed once the amyloid pathology was well developed, whereas Aβ deposition was enhanced in younger animals. In vitro studies indicated a more rapid endocytosis of APP in ABCA7 knock-out cells that is mechanistically consistent with the increased Aβ production. These in vitro and in vivo findings indicate a direct role of ABCA7 in amyloid processing that may be associated with its primary biological function to regulate endocytic pathways. Several potential loss-of-function ABCA7 mutations and deletions linked to Alzheimer disease that in some instances have a greater impact than apoE allelic variants have recently been identified. A reduction in ABCA7 expression or loss of function would be predicted to increase amyloid production and that may be a contributing factor in the associated Alzheimer disease susceptibility. PMID:26260791

  4. Amyloid-β Induces Hepatic Insulin Resistance In Vivo via JAK2

    OpenAIRE

    ZHANG Yi; Zhou, Ben; Deng, Bo; Zhang, Fang; Wu, Jingxia; Wang, Yuangao; Le, Yingying; Zhai, Qiwei

    2013-01-01

    Amyloid-β (Aβ), a natural product of cell metabolism, plays a key role in the pathogenesis of Alzheimer’s disease (AD). Epidemiological studies indicate patients with AD have an increased risk of developing type 2 diabetes mellitus (T2DM). Aβ can induce insulin resistance in cultured hepatocytes by activating the JAK2/STAT3/SOCS-1 signaling pathway. Amyloid precursor protein and presenilin 1 double-transgenic AD mouse models with increased circulating Aβ level show impaired glucose/insulin to...

  5. Expression and processing of fluorescent fusion proteins of amyloid precursor protein (APP)☆

    OpenAIRE

    Coughlan, Kathleen; Huang, Xiangping; He, Xiangyuan; Chung, Charlotte H.Y.; Li, Guangpu; Tang, Jordan

    2013-01-01

    Processing of β-amyloid precursor protein (APP) by β- and γ-secretases in neurons produces amyloid-β (Aβ), whose excess accumulation leads to Alzheimer’s disease (AD). Knowledge on subcellular trafficking pathways of APP and its fragments is important for the understanding of AD pathogenesis. We designed fusion proteins comprising a C-terminal fragment of APP (app) and fluorescent proteins GFP (G) and DsRed (D) to permit the tracking of the fusion proteins and fragments in cells. CAD cells ex...

  6. The relationship between complement factor C3, APOE ε4, amyloid and tau in Alzheimer's disease.

    Science.gov (United States)

    Bonham, Luke W; Desikan, Rahul S; Yokoyama, Jennifer S

    2016-01-01

    Inflammation is becoming increasingly recognized as an important contributor to Alzheimer's disease (AD) pathogenesis. As a part of the innate immune system, the complement cascade enhances the body's ability to destroy and remove pathogens and has recently been shown to influence Alzheimer's associated amyloid and tau pathology. However, little is known in humans about the effects of the complement system and genetic modifiers of AD risk like the ε4 allele of apolioprotein E (APOE ε4) on AD pathobiology. We evaluated cerebrospinal fluid (CSF) protein levels from 267 individuals clinically diagnosed as cognitively normal, mild cognitive impairment, and AD. Using linear models, we assessed the relationship between APOE ε4 genotype, CSF Complement 3 (C3), CSF amyloid-β (amyloid) and CSF hyperphosphorylated tau (ptau). We found a significant interaction between APOE ε4 and CSF C3 on both CSF amyloid and CSF ptau. We also found that CSF C3 is only associated with CSF ptau after accounting for CSF amyloid. Our results support a conceptual model of the AD pathogenic cascade where a synergistic relationship between the complement cascade (C3) and APOE ε4 results in elevated Alzheimer's neurodegeneration and in turn, amyloid further regulates the effect of the complement cascade on downstream tau pathology. PMID:27357286

  7. Differential X-ray phase contrast tomography of Alzheimer plaques in mouse models: perspectives for drug development and clinical imaging techniques

    International Nuclear Information System (INIS)

    Alzheimer's disease (AD) is a looming threat on an ever-ageing population, with devastating effects on the human intellect. A particular characteristic lesion — the extracellular amyloid plaque — accumulates in the brain of AD patients during the course of the disease, and could therefore be used to monitor the progression of the disease, years before the first neurological symptoms appear. In addition, strategies for drug intervention in AD are often based on amyloid reduction, since amyloid plaques are hypothesized to be involved in a chain of reactions leading to the death of neurons. Developments in both fields would benefit from a microscopic technique that is capable of single plaque imaging, ideally in 3D. While such a non-destructive, single-plaque imaging technique does not yet exist for humans, it has been recently shown that synchrotron based differential X-ray phase contrast imaging can be used to visualize individual plaques at μm resolution in mouse models of AD ex-vivo. This method, which relies on a grating interferometer to measure refraction angles induced by fluctuations in the refractive index, yields a precise three-dimensional distribution of single plaques. These data could not only improve the understanding of the evolution of AD or the effectiveness of drugs, but could also help to improve reliable markers for current and future non-invasive clinical imaging techniques. In particular, validation of PET markers with small animal models could be rapidly carried out by co-registration of PET and DPC signals.

  8. Pathogenesis of Parkinson's disease

    OpenAIRE

    Riederer, Peter; Lange, Klaus W.

    1992-01-01

    The importance of genetic aspects, ageing, environmental factors, head trauma, defective mitochondrial respiration, altered iron metabolism, oxidative stress and glutamatergic overactivity of the basal ganglia in the pathogenesis of Parkinson's disease (PD) are considered in this review.

  9. Towards a Pharmacophore for Amyloid

    Energy Technology Data Exchange (ETDEWEB)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David (UCLA)

    2011-09-16

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of {beta}-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. The devastating and incurable dementia known as Alzheimer's disease affects the thinking, memory, and behavior of dozens of millions of people worldwide. Although amyloid fibers and oligomers of two proteins, tau and amyloid-{beta}, have been identified in association with this disease, the development of diagnostics and therapeutics has proceeded to date in a near vacuum of information about their structures. Here we report the first atomic structures of small molecules bound to amyloid. These are of the dye orange-G, the natural compound curcumin, and the Alzheimer's diagnostic compound DDNP bound to amyloid-like segments of tau and amyloid-{beta}. The structures reveal the molecular framework of small-molecule binding, within cylindrical cavities running along the {beta}-spines of the fibers. Negatively charged orange-G wedges into a specific binding site between two sheets of the fiber, combining apolar binding with electrostatic interactions, whereas uncharged compounds slide along the cavity. We observed that different amyloid polymorphs bind different small molecules, revealing that a

  10. The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1-42 Species into Nontoxic Amyloid Fibers with Altered Properties.

    Science.gov (United States)

    Civitelli, Livia; Sandin, Linnea; Nelson, Erin; Khattak, Sikander Iqbal; Brorsson, Ann-Christin; Kågedal, Katarina

    2016-04-22

    Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic Aβ species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting Aβ-mediated cytotoxicity. Moreover, p-FTAA bound to early formed Aβ species and induced a rapid formation of β-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable Aβ species that were nontoxic which indicates that p-FTAA might have therapeutic potential. PMID:26907684

  11. The Luminescent Oligothiophene p-FTAA Converts Toxic Aβ1–42 Species into Nontoxic Amyloid Fibers with Altered Properties*

    Science.gov (United States)

    Civitelli, Livia; Sandin, Linnea; Nelson, Erin; Khattak, Sikander Iqbal; Kågedal, Katarina

    2016-01-01

    Aggregation of the amyloid-β peptide (Aβ) in the brain leads to the formation of extracellular amyloid plaques, which is one of the pathological hallmarks of Alzheimer disease (AD). It is a general hypothesis that soluble prefibrillar assemblies of the Aβ peptide, rather than mature amyloid fibrils, cause neuronal dysfunction and memory impairment in AD. Thus, reducing the level of these prefibrillar species by using molecules that can interfere with the Aβ fibrillation pathway may be a valid approach to reduce Aβ cytotoxicity. Luminescent-conjugated oligothiophenes (LCOs) have amyloid binding properties and spectral properties that differ when they bind to protein aggregates with different morphologies and can therefore be used to visualize protein aggregates. In this study, cell toxicity experiments and biophysical studies demonstrated that the LCO p-FTAA was able to reduce the pool of soluble toxic Aβ species in favor of the formation of larger insoluble nontoxic amyloid fibrils, there by counteracting Aβ-mediated cytotoxicity. Moreover, p-FTAA bound to early formed Aβ species and induced a rapid formation of β-sheet structures. These p-FTAA generated amyloid fibrils were less hydrophobic and more resistant to proteolysis by proteinase K. In summary, our data show that p-FTAA promoted the formation of insoluble and stable Aβ species that were nontoxic which indicates that p-FTAA might have therapeutic potential. PMID:26907684

  12. A Genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology

    OpenAIRE

    Matarin, M.; Perona, M.; D.A. Salih; Yasvoina, M.; Cummings, D. M.; Liu, W.; NahabooSolim, M. A.; Moens, T. G.; Paublete, R. M.; Ali, S. S.; Edwards, F. A.; Guelfi, S.; Hardy, J.; Latcham, J.; Fulleylove, M.

    2015-01-01

    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. N...

  13. Robust amyloid clearance in a mouse model of AD provides novel insights into the mechanism of Aβ immunotherapy

    OpenAIRE

    Wang, Allan; Das, Pritam; Switzer, Robert C.; Golde, Todd E.; Jankowsky, Joanna L.

    2011-01-01

    Many new therapeutics for Alzheimer's disease delay the accumulation of Aβ in transgenic mice, but evidence for clearance of pre-existing plaques is often lacking. Here we demonstrate that anti-Aβ immunotherapy combined with suppression of Aβ synthesis allows significant removal of antecedent deposits. We treated amyloid-bearing tet-off APP mice with doxycycline to suppress transgenic Aβ production before initiating a 12 week course of passive immunization. Animals remained on doxycycline for...

  14. β-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or β-amyloid deposits

    OpenAIRE

    Malm, Tarja; Ort, Michael; Tähtivaara, Leena; Jukarainen, Niko; Goldsteins, Gundars; Puoliväli, Jukka; Nurmi, Antti; Pussinen, Raimo; Ahtoniemi, Toni; Miettinen, Taina-Kaisa; Kanninen, Katja; Leskinen, Suvi; Vartiainen, Nina; Yrjänheikki, Juha; Laatikainen, Reino

    2006-01-01

    β-Amyloid (Aβ) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Aβ deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Aβ in animal models results in Aβ deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Aβ and whether inflammation is required for Aβ-induce...

  15. Expression of apolipoprotein serum amyloid A mRNA in human atherosclerotic lesions and cultured vascular cells: implications for serum amyloid A function.

    OpenAIRE

    Meek, R L; Urieli-Shoval, S.; Benditt, E. P.

    1994-01-01

    Altered lipoprotein metabolism and vascular injury are considered to be major parts of the pathogenesis of atherosclerotic lesions. Serum amyloid A (SAA) is a family of acute-phase reactants found residing mainly on high density lipoproteins (HDL) in the circulation. Several functions for the SAAs have been proposed that could be important in atherosclerosis. These include involvement in cholesterol metabolism, participation in detoxification, depression of immune responses, and interference ...

  16. Platelet activation and platelet-monocyte aggregate formation by the atherosclerotic plaque lipid lysophosphatidic acid

    OpenAIRE

    Haserück, Nadine

    2007-01-01

    Oxidized LDL and platelets play a central role in the pathogenesis of atherosclerosis and ischemic cardiovascular diseases. Lysophosphatidic acid (LPA) is a thrombogenic substance that accumulates in mildly-oxidized LDL and in human atherosclerotic lesions, and is responsible for the initial platelet activation, shape change, induced by mildly-oxidized LDL and extracts of lipid-rich atherosclerotic plaques (Siess et al., 1999 Proc Natl Acad Sci USA 1999). LPA directly induced platelet shape c...

  17. Atherosclerosis and Atheroma Plaque Rupture: Imaging Modalities in the Visualization of Vasa Vasorum and Atherosclerotic Plaques

    OpenAIRE

    2014-01-01

    Invasive angiography has been widely accepted as the gold standard to diagnose cardiovascular pathologies. Despite its superior resolution of demonstrating atherosclerotic plaque in terms of degree of lumen stenosis, the morphological assessment for the plaque is insufficient for the analysis of plaque components, and therefore, unable to predict the risk status or vulnerability of atherosclerotic plaque. There is an increased body of evidence to show that the vasa vasorum play an important r...

  18. Fibrillation of β amyloid peptides in the presence of phospholipid bilayers and the consequent membrane disruption.

    Science.gov (United States)

    Qiang, Wei; Yau, Wai-Ming; Schulte, Jürgen

    2015-01-01

    Fibrillation of β amyloid (Aβ) peptides and the accumulation of amyloid plaques are considered as an important clinical hallmark to identify Alzheimer's disease (AD). The physiological connection between Aβ plaques and the disruption of neuronal cells has not been clearly understood. One hypothesis to explain the Aβ neurotoxicity is that the fibrillation process induces disruption to the cellular membrane. We studied the Aβ fibrillation process in two biologically relevant conditions with the peptide either pre-incorporated into or externally added to the synthetic phospholipid bilayers. These two sample preparation conditions mimic the physiological membrane proximities of Aβ peptides before and after the enzymatic cleavage of amyloid precursor protein (APP). Using thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM), we were able to monitor the kinetics and morphological evolution of fibril formation, which was highly sensitive to the two sample preparation protocols. While the external addition protocol generates long and mature fibrils through normal fibrillation process, the pre-incubation protocol was found to stabilize the immature protofibrils. Fluorescence spectroscopy studies with doubly-labeled phospholipids indicated that there may be a lipid uptake process associated with the fibril formation. Solid state nuclear magnetic resonance (NMR) spectroscopy provided evidence for high resolution structural variations in fibrils formed with different protocols, and in particular the stabilization of long-range contact between N- and C-terminal β strands. In addition, disruption of phospholipid bilayers was supported by measurements with ³¹P chemical shifts and relaxation time constants. PMID:24769158

  19. Innate immunity in the pathogenesis of psoriasis.

    LENUS (Irish Health Repository)

    Sweeney, Cheryl M

    2011-12-01

    Psoriasis is a common, immune-mediated inflammatory skin disorder. T helper(h)1 and Th17 lymphocytes contribute to the pathogenesis of psoriasis through the release of inflammatory cytokines that promote further recruitment of immune cells, keratinocyte proliferation and sustained inflammation. The innate immune system is the first line of defence against infection and plays a crucial role in the initiation of the adaptive immune response. The presence of innate immune cells and their products in psoriatic skin plaques suggests a role for innate immunity in this disease. In addition, the innate immune system can direct the development of pathogenic Th cells in psoriasis. In this article, we will summarise the role of the innate immune system in psoriasis with particular emphasis on the role of cytokines, signalling pathways and cells of the innate immune system.

  20. Proliferation in the Alzheimer Hippocampus Is due to Microglia, Not Astroglia, and Occurs at Sites of Amyloid Deposition

    Directory of Open Access Journals (Sweden)

    Michael W. Marlatt

    2014-01-01

    Full Text Available Microglia and astrocytes contribute to Alzheimer’s disease (AD etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were colabeled with Iba1+, indicating that particularly microglia contribute to proliferation in AD. Proliferating Iba1+ cells was specifically seen within the borders of amyloid plaques, indicative of an active involvement in, or response to, plaque accumulation. Thus, consistent with animal studies, proliferation in the AD hippocampus is due to microglia, occurs in close proximity of plaque pathology, and may contribute to the neuroinflammation common in AD.

  1. Mechanical Stresses in Carotid Plaques

    DEFF Research Database (Denmark)

    Samuel, Samuel Alberg

    af stenose. Den tredje artikel; “The Effect of Plaque Morphology on Fibrous Cap Stress Levels”, er en parametrisk analyse af den relative betydning af lipidkernens størrelse, den fibrøse kappes tykkelse, graden af forsnævring og lipidkernens placering for stress-niveauet i den fibrøse kappe. Alle...... patienter med aterosklerose i a. carotis kunne derfor med fordel ændres til at inkludere morfologiske markører. Nylige fremskridt indenfor hard- og software har muliggjort beregning af de kræfter, som påvirker plaques og de resulterende stress-niveauer. Jævnfør plaquerupturs traumatiske natur, regnes de...... mekaniske kræfter, som påvirker den fibrøse kappe, for at være en medvirkende årsag til plaqueruptur. Endvidere er stress-niveauerne i den fibrøse kappe en risikomarkør, som påvirkes af såvel den fibrøse kappetykkelse som lipid kerne størrelsen, blodtryk og graden af forsnævring. Imidlertid har hidtidige...

  2. Is pathological aging a successful resistance against amyloid-beta or preclinical Alzheimer's disease?

    Science.gov (United States)

    Murray, Melissa E; Dickson, Dennis W

    2014-01-01

    Individuals with pathological aging, a form of cerebral amyloidosis in older people, have widespread extracellular amyloid-beta (Aβ) senile plaque deposits in the setting of limited neurofibrillary tau pathology. Unlike the characteristic finding of antemortem cognitive impairment in Alzheimer's disease patients, individuals with pathological aging usually lack cognitive impairment despite similar Aβ senile plaque burdens. It has been hypothesized that protective or resistance factors may underlie pathological aging, thus minimizing or preventing deleterious effects on cognition. Despite increasing interest and recognition, a review of the literature remains challenging given the range of terms used to describe pathological aging. This debate briefly reviews neuropathologic and biochemical evidence that pathological aging individuals have resistance factors to Aβ plaque pathology. Additionally, we will discuss evidence of pathological aging as an intermediate between normal individuals and Alzheimer's disease patients, and discuss protective or resistance factors against vascular disease and neurofibrillary pathology. Lastly, we will emphasize the need for longitudinal biomarker evidence using amyloid positron emission tomography, which will provide a better understanding of the kinetics of Aβ deposition in pathological aging. PMID:25031637

  3. Current status of vulnerable plaque detection.

    LENUS (Irish Health Repository)

    Sharif, Faisal

    2012-02-01

    Critical coronary stenoses have been shown to contribute to only a minority of acute coronary syndromes (ACS) and sudden cardiac death. Autopsy studies have identified a subgroup of high-risk patients with disrupted vulnerable plaque and modest stenosis. Consequently, a clinical need exists to develop methods to identify these plaques prospectively before disruption and clinical expression of disease. Recent advances in invasive and noninvasive imaging techniques have shown the potential to identify these high-risk plaques. The anatomical characteristics of the vulnerable plaque such as thin cap fibroatheroma and lipid pool can be identified with angioscopy, high frequency intravascular ultrasound, intravascular MRI, and optical coherence tomography. Efforts have also been made to recognize active inflammation in high-risk plaques using intravascular thermography. Plaque chemical composition by measuring electromagnetic radiation using spectroscopy is also an emerging technology to detect vulnerable plaques. Noninvasive imaging with MRI, CT, and PET also holds the potential to differentiate between low and high-risk plaques. However, at present none of these imaging modalities are able to detect vulnerable plaque neither has been shown to definitively predict outcome. Nevertheless in contrast, there has been a parallel development in the physiological assessment of advanced atherosclerotic coronary artery disease. Thus recent trials using fractional flow reserve in patients with modest non flow-limiting stenoses have shown that deferral of PCI with optimal medical therapy in these patients is superior to coronary intervention. Further trials are needed to provide more information regarding the natural history of high-risk but non flow-limiting plaque to establish patient-specific targeted therapy and to refine plaque stabilizing strategies in the future.

  4. Antroquinonol Lowers Brain Amyloid-β Levels and Improves Spatial Learning and Memory in a Transgenic Mouse Model of Alzheimer’s Disease

    OpenAIRE

    Wen-Han Chang; Chen, Miles C.; Cheng, Irene H.

    2015-01-01

    Alzheimer’s disease (AD) is the most common form of dementia. The deposition of brain amyloid-β peptides (Aβ), which are cleaved from amyloid precursor protein (APP), is one of the pathological hallmarks of AD. Aβ-induced oxidative stress and neuroinflammation play important roles in the pathogenesis of AD. Antroquinonol, a ubiquinone derivative isolated from Antrodia camphorata, has been shown to reduce oxidative stress and inflammatory cytokines via activating the nuclear transcription fact...

  5. The pattern of amyloid accumulation in the brains of adults with Down syndrome

    Science.gov (United States)

    Annus, Tiina; Wilson, Liam R.; Hong, Young T.; Acosta–Cabronero, Julio; Fryer, Tim D.; Cardenas–Blanco, Arturo; Smith, Robert; Boros, Istvan; Coles, Jonathan P.; Aigbirhio, Franklin I.; Menon, David K.; Zaman, Shahid H.; Nestor, Peter J.; Holland, Anthony J.

    2016-01-01

    Introduction Adults with Down syndrome (DS) invariably develop Alzheimer's disease (AD) neuropathology. Understanding amyloid deposition in DS can yield crucial information about disease pathogenesis. Methods Forty-nine adults with DS aged 25–65 underwent positron emission tomography with Pittsburgh compound–B (PIB). Regional PIB binding was assessed with respect to age, clinical, and cognitive status. Results Abnormal PIB binding became evident from 39 years, first in striatum followed by rostral prefrontal-cingulo-parietal regions, then caudal frontal, rostral temporal, primary sensorimotor and occipital, and finally parahippocampal cortex, thalamus, and amygdala. PIB binding was related to age, diagnostic status, and cognitive function. Discussion PIB binding in DS, first appearing in striatum, began around age 40 and was strongly associated with dementia and cognitive decline. The absence of a substantial time lag between amyloid accumulation and cognitive decline contrasts to sporadic/familial AD and suggests this population's suitability for an amyloid primary prevention trial. PMID:26362596

  6. Cerebral amyloid angiopathy presenting as a posterior leukoencephalopathy: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Maramattom Boby Varkey

    2004-10-01

    Full Text Available Cerebral amyloid angiopathy (CAA is well known to present with lobar intracerebral hemorrhage, dementia or transient neurological events. White matter changes with CAA have only been recently described and can be seen with either sporadic or familial CAA. We present a 50-year-old man with rapidly progressive dementia in whom MRI brain showed symmetrical white matter changes in the parieto-occipital regions. Brain biopsy revealed changes of CAA along with features of Alzheimer′s disease. Immunohistochemistry revealed amyloid beta protein. The subcortical lesions were thought to occur from hypoperfusion of the distal white matter. The role of amyloid in the pathogenesis of CAA and the mechanism of leukoencephalopathy are discussed.

  7. Ultrasonic echolucent carotid plaques predict future strokes

    DEFF Research Database (Denmark)

    Grønholdt, Marie-Louise; Nordestgaard, B G; Schroeder, T V; Vorstrup, S; Sillesen, H

    2001-01-01

    We tested prospectively the hypothesis that stroke development can be predicted by echolucency of carotid atherosclerotic plaques in previously symptomatic and asymptomatic patients.......We tested prospectively the hypothesis that stroke development can be predicted by echolucency of carotid atherosclerotic plaques in previously symptomatic and asymptomatic patients....

  8. Oral biofilm models for mechanical plaque removal

    NARCIS (Netherlands)

    Verkaik, Martinus J.; Busscher, Henk J.; Rustema-Abbing, Minie; Slomp, Anje M.; Abbas, Frank; van der Mei, Henny C.

    2010-01-01

    In vitro plaque removal studies require biofilm models that resemble in vivo dental plaque. Here, we compare contact and non-contact removal of single and dual-species biofilms as well as of biofilms grown from human whole saliva in vitro using different biofilm models. Bacteria were adhered to a sa

  9. Toxic β-Amyloid (Aβ) Alzheimer's Ion Channels: From Structure to Function and Design

    Science.gov (United States)

    Nussinov, Ruth

    2012-02-01

    Full-length amyloid beta peptides (Aβ1-40/42) form neuritic amyloid plaques in Alzheimer's disease (AD) patients and are implicated in AD pathology. Recent biophysical and cell biological studies suggest a direct mechanism of amyloid beta toxicity -- ion channel mediated loss of calcium homeostasis. Truncated amyloid beta fragments (Aβ11-42 and Aβ17-42), commonly termed as non-amyloidogenic are also found in amyloid plaques of Alzheimer's disease (AD) and in the preamyloid lesions of Down's syndrome (DS), a model system for early onset AD study. Very little is known about the structure and activity of these smaller peptides although they could be key AD and DS pathological agents. Using complementary techniques of explicit solvent molecular dynamics (MD) simulations, atomic force microscopy (AFM), channel conductance measurements, cell calcium uptake assays, neurite degeneration and cell death assays, we have shown that non-amyloidogenic Aβ9-42 and Aβ17-42 peptides form ion channels with loosely attached subunits and elicit single channel conductances. The subunits appear mobile suggesting insertion of small oligomers, followed by dynamic channel assembly and dissociation. These channels allow calcium uptake in APP-deficient cells and cause neurite degeneration in human cortical neurons. Channel conductance, calcium uptake and neurite degeneration are selectively inhibited by zinc, a blocker of amyloid ion channel activity. Thus truncated Aβ fragments could account for undefined roles played by full length Aβs and provide a novel mechanism of AD and DS pathology. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets are highly polymorphic, and spontaneously break into loosely interacting dynamic units (though still maintaining ion channel structures as imaged with AFM), that associate and dissociate leading to toxic ion flux. This sharply contrasts intact conventional gated ion channels that consist of tightly

  10. Amyloid-linked cellular toxicity triggered by bacterial inclusion bodies

    International Nuclear Information System (INIS)

    The aggregation of proteins in the form of amyloid fibrils and plaques is the characteristic feature of some pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. The mechanisms by which the aggregation processes result in cell damage are under intense investigation but recent data indicate that prefibrillar aggregates are the most proximate mediators of toxicity rather than mature fibrils. Since it has been shown that prefibrillar forms of the nondisease-related misfolded proteins are highly toxic to cultured mammalian cells we have studied the cytoxicity associated to bacterial inclusion bodies that have been recently described as protein deposits presenting amyloid-like structures. We have proved that bacterial inclusion bodies composed by a misfolding-prone β-galactosidase fusion protein are clearly toxic for mammalian cells but the β-galactosidase wild type enzyme forming more structured thermal aggregates does not impair cell viability, despite it also binds and enter into the cells. These results are in the line that the most cytotoxic aggregates are early prefibrilar assemblies but discard the hypothesis that the membrane destabilization is Key event to subsequent disruption of cellular processes, such as ion balance, oxidative state and the eventually cell death

  11. Aspects of structural landscape of human islet amyloid polypeptide

    Energy Technology Data Exchange (ETDEWEB)

    He, Jianfeng, E-mail: hjf@bit.edu.cn; Dai, Jin, E-mail: daijing491@gmail.com [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Li, Jing, E-mail: jinglichina@139.com [Institute of Biopharmaceutical Research, Yangtze River Pharmaceutical Group Beijing Haiyan Pharmaceutical Co., Ltd, Beijing 102206 (China); Peng, Xubiao, E-mail: xubiaopeng@gmail.com [Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Niemi, Antti J., E-mail: Antti.Niemi@physics.uu.se [School of Physics, Beijing Institute of Technology, Beijing 100081 (China); Department of Physics and Astronomy, Uppsala University, P.O. Box 803, S-75108 Uppsala (Sweden); Laboratoire de Mathematiques et Physique Theorique CNRS UMR 6083, Fédération Denis Poisson, Université de Tours, Parc de Grandmont, F37200 Tours (France)

    2015-01-28

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation.

  12. Aspects of structural landscape of human islet amyloid polypeptide

    International Nuclear Information System (INIS)

    The human islet amyloid polypeptide (hIAPP) co-operates with insulin to maintain glycemic balance. It also constitutes the amyloid plaques that aggregate in the pancreas of type-II diabetic patients. We have performed extensive in silico investigations to analyse the structural landscape of monomeric hIAPP, which is presumed to be intrinsically disordered. For this, we construct from first principles a highly predictive energy function that describes a monomeric hIAPP observed in a nuclear magnetic resonance experiment, as a local energy minimum. We subject our theoretical model of hIAPP to repeated heating and cooling simulations, back and forth between a high temperature regime where the conformation resembles a random walker and a low temperature limit where no thermal motions prevail. We find that the final low temperature conformations display a high level of degeneracy, in a manner which is fully in line with the presumed intrinsically disordered character of hIAPP. In particular, we identify an isolated family of α-helical conformations that might cause the transition to amyloidosis, by nucleation

  13. PLAQUE ASSAY OF NEWCASTLE DISEASE VIRUS

    Directory of Open Access Journals (Sweden)

    B. Sardjono

    2012-09-01

    Full Text Available The Newcastle disease virus (NDV was isolated from a 3 months-old indigenous chicken (buras or kampung chicken which showed clinical signs of Newcastle disease (ND. For viral isolation a small part of the spleen and lung were inoculated into 10 days-old embryonated chicken eggs. The physical characteristics of the isolate (A/120 were studied. The hemagglutination of chicken red blood cell showed slow elution, thermostability of hemagglutinin at 56°C was 120 minutes. The vims was able to agglutinate horse erythrocytes but not those of sheep. The biological characteristics on mean death time (MDT of embryonated chicken egg and plaque morphology on chicken embryo fibroblast (CEF primary cell cultures were studied. The MDT was 56 hours, the isolate was velogenic NDV. There were three different plaque morphologies on CEF : 2 mm clear plaques, 1 mm clear plaques, and minute clear plaques which were visible only with microscopic examination.

  14. Pathogenesis of Hepatic Encephalopathy

    Directory of Open Access Journals (Sweden)

    Irena Ciećko-Michalska

    2012-01-01

    Full Text Available Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.

  15. The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

    Directory of Open Access Journals (Sweden)

    Cristina Grossi

    Full Text Available The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet, the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

  16. Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease.

    Science.gov (United States)

    Ryan, Natalie S; Biessels, Geert-Jan; Kim, Lois; Nicholas, Jennifer M; Barber, Philip A; Walsh, Phoebe; Gami, Priya; Morris, Huw R; Bastos-Leite, António J; Schott, Jonathan M; Beck, Jon; Mead, Simon; Chavez-Gutierrez, Lucia; de Strooper, Bart; Rossor, Martin N; Revesz, Tamas; Lashley, Tammaryn; Fox, Nick C

    2015-12-01

    Familial Alzheimer's disease (FAD) treatment trials raise interest in the variable occurrence of cerebral amyloid angiopathy (CAA); an emerging important factor in amyloid-modifying therapy. Previous pathological studies reported particularly severe CAA with postcodon 200 PSEN1 mutations and amyloid beta coding domain APP mutations. As CAA may manifest as white matter hyperintensities (WMH) on magnetic resonance imaging, particularly posteriorly, we investigated WMH in 52 symptomatic FAD patients for associations with mutation position. WMH were visually rated in 39 PSEN1 (18 precodon 200); 13 APP mutation carriers and 25 healthy controls. Ten PSEN1 mutation carriers (5 precodon 200) had postmortem examination. Increased WMH were observed in the PSEN1 postcodon 200 group and in the single APP patient with an amyloid beta coding domain (p.Ala692Gly, Flemish) mutation. WMH burden on MRI correlated with severity of CAA and cotton wool plaques in several areas. The precodon 200 group had younger ages at onset, decreased axonal density and/or integrity, and a greater T-lymphocytic response in occipital deep white matter. Mutation site contributes to the phenotypic and pathological heterogeneity witnessed in FAD. PMID:26410308

  17. Preparation of Amyloid Immuno-Nanoparticles as Potential MRI Contrast Agents for Alzheimer's Disease Diagnosis.

    Science.gov (United States)

    Yin, Zhenyu; Yul, Tingting; Xu, Yun

    2015-09-01

    Alzheimer's disease (AD) is the most common form of dementia which is caused by accumulation in the brain of plaques made up of amyloid beta-peptide (Abeta). Research on nanosized systems indicated that nanoparticles (NPs) could pass across the blood-brain barrier (BBB) and improve the visibility of internal body structures in magnetic resonance imaging (MRI), which made it possible to aid the early diagnosis of AD. In this research study we synthesized magnetite nanoparticles by high-temperature solution-phase reaction, transferred into water based on a ligand exchange process and coated with meso-2,3-dimercaptosuccinic (DMSA). Subsequently, the anti-amyloid Abeta immunomagnetic nanoparticles (IMNPs) were prepared by grafting anti-amyloid antibodies on the surface of the DMSA-coated magnetic nanoparticles (MNPs). The enzyme linked immunosorbent assay (ELISA) method was introduced to evaluate the IMNPs activity and conjugation amount of antibodies. The biocompatibility of the IMNPs was tested by colony-forming assay. The results showed that the anti-amyloid Abeta IMNPs were biocompatible and biologically active, as well as effective in enhancing MRI solution, indicating that the IMNPs could be used as potential MRI contrast agents and targeted carriers for AD early diagnosis and therapy. PMID:26716196

  18. Cerebroprotective effect of Huanglian Jiedu decoction on amyloid protein precursor/presenilin-1 double transgenic mice

    Institute of Scientific and Technical Information of China (English)

    Xin Qiu; Guohua Chen; Gui Mei; Yuegu Wang; Kaixin Wang; Tao Wang; Pei Feng

    2011-01-01

    Huanglian Jiedu decoction (HLJDD) has been shown to improve cerebral blood flow, and reduce lipid peroxidation damage to the brain and its energy metabolism. The present study was designed to observe the cerebroprotective effect of HLJDD on an Alzheimer's disease rodent model,presenilin-1/amyloid protein precursor double transgenic mice. HLJDD reduced serum interleukin-6 and interleukin-1β levels, decreased β-amyloid precursor protein gene and senile plaque expression, resisted oxidation, and reduced free radical-induced injury, thereby improving the learning and memory of these mice. Moreover, HLJDD at 433 mg/kg per day exhibited better effects compared with that at 865 or 216 mg/kg per day, and donepezil hydrochloride at 30 mg/kg per day.Thus, these results suggest that HLJDD may have protective effects against Alzheimer's disease.

  19. Functional Amyloid Formation within Mammalian Tissue.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

  20. Nanomechanical properties of single amyloid fibrils

    Science.gov (United States)

    Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

    2012-06-01

    Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

  1. Multidetector row computed tomography may accurately estimate plaque vulnerability. Does MDCT accurately estimate plaque vulnerability? (Pro)

    International Nuclear Information System (INIS)

    Over the past decade, multidetector row computed tomography (MDCT) has become the most reliable and established of the noninvasive examination techniques for detecting coronary heart disease. Now MDCT is chasing intravascular ultrasound (IVUS) in terms of spatial resolution. Among the components of vulnerable plaque, MDCT may detect lipid-rich plaque, the lipid pool, and calcified spots using computed tomography number. Plaque components are detected by MDCT with high accuracy compared with IVUS and angioscopy when assessing vulnerable plaque. The TWINS study and TOGETHAR trial demonstrated that angioscopic loss of yellow color occurred independently of volumetric plaque change by statin therapy. These 2 studies showed that plaque stabilization and regression reflect independent processes mediated by different mechanisms and time course. Noncalcified plaque and/or low-density plaque was found to be the strongest predictor of cardiac events, regardless of lesion severity, and act as a potential marker of plaque vulnerability. MDCT may be an effective tool for early triage of patients with chest pain who have a normal electrocardiogram (ECG) and cardiac enzymes in the emergency department. MDCT has the potential ability to analyze coronary plaque quantitatively and qualitatively if some problems are resolved. MDCT may become an essential tool for detecting and preventing coronary artery disease in the future. (author)

  2. Multidetector row computed tomography may accurately estimate plaque vulnerability: does MDCT accurately estimate plaque vulnerability? (Pro).

    Science.gov (United States)

    Komatsu, Sei; Imai, Atsuko; Kodama, Kazuhisa

    2011-01-01

    Over the past decade, multidetector row computed tomography (MDCT) has become the most reliable and established of the noninvasive examination techniques for detecting coronary heart disease. Now MDCT is chasing intravascular ultrasound (IVUS) in terms of spatial resolution. Among the components of vulnerable plaque, MDCT may detect lipid-rich plaque, the lipid pool, and calcified spots using computed tomography number. Plaque components are detected by MDCT with high accuracy compared with IVUS and angioscopy when assessing vulnerable plaque. The TWINS study and TOGETHAR trial demonstrated that angioscopic loss of yellow color occurred independently of volumetric plaque change by statin therapy. These 2 studies showed that plaque stabilization and regression reflect independent processes mediated by different mechanisms and time course. Noncalcified plaque and/or low-density plaque was found to be the strongest predictor of cardiac events, regardless of lesion severity, and act as a potential marker of plaque vulnerability. MDCT may be an effective tool for early triage of patients with chest pain who have a normal ECG and cardiac enzymes in the emergency department. MDCT has the potential ability to analyze coronary plaque quantitatively and qualitatively if some problems are resolved. MDCT may become an essential tool for detecting and preventing coronary artery disease in the future. PMID:21532180

  3. Depolymerization of insulin amyloid fibrils by albumin-modified magnetic fluid

    Science.gov (United States)

    Siposova, Katarina; Kubovcikova, Martina; Bednarikova, Zuzana; Koneracka, Martina; Zavisova, Vlasta; Antosova, Andrea; Kopcansky, Peter; Daxnerova, Zuzana; Gazova, Zuzana

    2012-02-01

    Pathogenesis of amyloid-related diseases is associated with the presence of protein amyloid deposits. Insulin amyloids have been reported in a patient with diabetes undergoing treatment by injection of insulin and causes problems in the production and storage of this drug and in application of insulin pumps. We have studied the interference of insulin amyloid fibrils with a series of 18 albumin magnetic fluids (MFBSAs) consisting of magnetite nanoparticles modified by different amounts of bovine serum albumin (w/w BSA/Fe3O4 from 0.005 up to 15). We have found that MFBSAs are able to destroy amyloid fibrils in vitro. The extent of fibril depolymerization was affected by nanoparticle physical-chemical properties (hydrodynamic diameter, zeta potential and isoelectric point) determined by the BSA amount present in MFBSAs. The most effective were MFBSAs with lower BSA/Fe3O4 ratios (from 0.005 to 0.1) characteristic of about 90% depolymerizing activity. For the most active magnetic fluids (ratios 0.01 and 0.02) the DC50 values were determined in the range of low concentrations, indicating their ability to interfere with insulin fibrils at stoichiometric concentrations. We assume that the present findings represent a starting point for the application of the active MFBSAs as therapeutic agents targeting insulin amyloidosis.

  4. Depolymerization of insulin amyloid fibrils by albumin-modified magnetic fluid

    International Nuclear Information System (INIS)

    Pathogenesis of amyloid-related diseases is associated with the presence of protein amyloid deposits. Insulin amyloids have been reported in a patient with diabetes undergoing treatment by injection of insulin and causes problems in the production and storage of this drug and in application of insulin pumps. We have studied the interference of insulin amyloid fibrils with a series of 18 albumin magnetic fluids (MFBSAs) consisting of magnetite nanoparticles modified by different amounts of bovine serum albumin (w/w BSA/Fe3O4 from 0.005 up to 15). We have found that MFBSAs are able to destroy amyloid fibrils in vitro. The extent of fibril depolymerization was affected by nanoparticle physical–chemical properties (hydrodynamic diameter, zeta potential and isoelectric point) determined by the BSA amount present in MFBSAs. The most effective were MFBSAs with lower BSA/Fe3O4 ratios (from 0.005 to 0.1) characteristic of about 90% depolymerizing activity. For the most active magnetic fluids (ratios 0.01 and 0.02) the DC50 values were determined in the range of low concentrations, indicating their ability to interfere with insulin fibrils at stoichiometric concentrations. We assume that the present findings represent a starting point for the application of the active MFBSAs as therapeutic agents targeting insulin amyloidosis. (paper)

  5. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide

    OpenAIRE

    de Melo, Joana Barbosa; Agostinho, Paula; Oliveira, Catarina Resende

    2003-01-01

    Acetylcholinesterase (AChE) activity is increased within and around amyloid plaques, which are present in Alzheimer's disease (AD) patient's brain. In this study, using cultured retinal cells as a neuronal model, we analyzed the effect of the synthetic peptide A[beta]25-35 on the activity of AChE, the degradation enzyme of acetylcholine, as well as the involvement of oxidative stress in this process. The activity of AChE was increased when retinal cells were incubated with A[beta]25-35 (25 [m...

  6. Transthyretin cardiac amyloidosis: pathogenesis, treatments, and emerging role in heart failure with preserved ejection fraction.

    Science.gov (United States)

    Ton, Van-Khue; Mukherjee, Monica; Judge, Daniel P

    2014-01-01

    Transthyretin (TTR) amyloidosis causes heart failure from cardiac deposition of TTR amyloid fibrils, the by-product of TTR homotetramer disassembly. Wild-type (WT) TTR deposition leads to senile amyloidosis, predominantly manifesting with cardiomyopathy. Missense mutations in the TTR gene result in familial TTR amyloidosis. Certain mutations are more likely to affect the heart, while others cause more neurologic involvement. Extracellular fibril deposition triggers intracellular stress response, upregulation of the inflammatory cascades, apoptosis, and organ dysfunction. Recent studies suggest that TTR cardiac amyloid may be a significant contributor to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Summarized in this review are the molecular pathways underlying the cellular toxicity of TTR amyloid fibrils and the emerging therapies aimed at TTR tetramer stabilization, abrogation of TTR synthesis in the liver, or inhibition of amyloidogenesis. PMID:25628512

  7. Oleuropein aglycone protects transgenic C. elegans strains expressing Aβ42 by reducing plaque load and motor deficit.

    Directory of Open Access Journals (Sweden)

    Luisa Diomede

    Full Text Available The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42 in the brain is the characteristic feature of Alzheimer's disease (AD. Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM, a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE, the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

  8. Atherosclerosis and Atheroma Plaque Rupture: Imaging Modalities in the Visualization of Vasa Vasorum and Atherosclerotic Plaques

    Directory of Open Access Journals (Sweden)

    Zhonghua Sun

    2014-01-01

    Full Text Available Invasive angiography has been widely accepted as the gold standard to diagnose cardiovascular pathologies. Despite its superior resolution of demonstrating atherosclerotic plaque in terms of degree of lumen stenosis, the morphological assessment for the plaque is insufficient for the analysis of plaque components, and therefore, unable to predict the risk status or vulnerability of atherosclerotic plaque. There is an increased body of evidence to show that the vasa vasorum play an important role in the initiation, progression, and complications of atherosclerotic plaque leading to major adverse cardiac events. This paper provides an overview of the evidence-based reviews of various imaging modalities with regard to their potential value for comprehensive characterization of the composition, burden, and neovascularization of atherosclerotic plaque.

  9. Atherosclerosis and atheroma plaque rupture: imaging modalities in the visualization of vasa vasorum and atherosclerotic plaques.

    Science.gov (United States)

    Sun, Zhonghua

    2014-01-01

    Invasive angiography has been widely accepted as the gold standard to diagnose cardiovascular pathologies. Despite its superior resolution of demonstrating atherosclerotic plaque in terms of degree of lumen stenosis, the morphological assessment for the plaque is insufficient for the analysis of plaque components, and therefore, unable to predict the risk status or vulnerability of atherosclerotic plaque. There is an increased body of evidence to show that the vasa vasorum play an important role in the initiation, progression, and complications of atherosclerotic plaque leading to major adverse cardiac events. This paper provides an overview of the evidence-based reviews of various imaging modalities with regard to their potential value for comprehensive characterization of the composition, burden, and neovascularization of atherosclerotic plaque. PMID:24688380

  10. Amyloid formation: functional friend or fearful foe?

    Science.gov (United States)

    Bergman, P; Roan, N R; Römling, U; Bevins, C L; Münch, J

    2016-08-01

    Amyloid formation has been most studied in the context of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, as well as in amyloidosis. However, it is becoming increasingly clear that amyloid is also present in the healthy setting; for example nontoxic amyloid formation is important for melanin synthesis and in innate immunity. Furthermore, bacteria have mechanisms to produce functional amyloid structures with important roles in bacterial physiology and interaction with host cells. Here, we will discuss some novel aspects of fibril-forming proteins in humans and bacteria. First, the amyloid-forming properties of the antimicrobial peptide human defensin 6 (HD6) will be considered. Intriguingly, unlike other antimicrobial peptides, HD6 does not kill bacteria. However, recent data show that HD6 can form amyloid structures at the gut mucosa with strong affinity for bacterial surfaces. These so-called nanonets block bacterial invasion by entangling the bacteria in net-like structures. Next, the role of functional amyloid fibrils in human semen will be discussed. These fibrils were discovered through their property to enhance HIV infection but they may also have other yet unknown functions. Finally, the role of amyloid formation in bacteria will be reviewed. The recent finding that bacteria can make amyloid in a controlled fashion without toxic effects is of particular interest and may have implications for human disease. The role of amyloid in health and disease is beginning to be unravelled, and here, we will review some of the most recent findings in this exciting area. PMID:27151743

  11. Evaluation of Carotid Plaque Using Ultrasound Imaging

    Science.gov (United States)

    2016-01-01

    Traditional risk factors for predicting of cardiovascular disease are not always effective predictors for development of cardiovascular events. This review summarizes several newly developed noninvasive imaging techniques for evaluating carotid plaques and their role in cardiovascular disease risk.

  12. Chronic rhinosinusitis pathogenesis.

    Science.gov (United States)

    Stevens, Whitney W; Lee, Robert J; Schleimer, Robert P; Cohen, Noam A

    2015-12-01

    There are a variety of medical conditions associated with chronic sinonasal inflammation, including chronic rhinosinusitis (CRS) and cystic fibrosis. In particular, CRS can be divided into 2 major subgroups based on whether nasal polyps are present or absent. Unfortunately, clinical treatment strategies for patients with chronic sinonasal inflammation are limited, in part because the underlying mechanisms contributing to disease pathology are heterogeneous and not entirely known. It is hypothesized that alterations in mucociliary clearance, abnormalities in the sinonasal epithelial cell barrier, and tissue remodeling all contribute to the chronic inflammatory and tissue-deforming processes characteristic of CRS. Additionally, the host innate and adaptive immune responses are also significantly activated and might be involved in pathogenesis. Recent advancements in the understanding of CRS pathogenesis are highlighted in this review, with special focus placed on the roles of epithelial cells and the host immune response in patients with cystic fibrosis, CRS without nasal polyps, or CRS with nasal polyps. PMID:26654193

  13. Schwannomas and their pathogenesis.

    Science.gov (United States)

    Hilton, David A; Hanemann, Clemens Oliver

    2014-04-01

    Schwannomas may occur spontaneously, or in the context of a familial tumor syndrome such as neurofibromatosis type 2 (NF2), schwannomatosis and Carney's complex. Schwannomas have a variety of morphological appearances, but they behave as World Health Organization (WHO) grade I tumors, and only very rarely undergo malignant transformation. Central to the pathogenesis of these tumors is loss of function of merlin, either by direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation. The genetic pathways and morphological features of schwannomas associated with different genetic syndromes will be discussed. Merlin has multiple functions, including within the nucleus and at the cell membrane, and this review summarizes our current understanding of the mechanisms by which merlin loss is involved in schwannoma pathogenesis, highlighting potential areas for therapeutic intervention. PMID:24450866

  14. A new inexpensive customized plaque for choroidal melanoma iodine-125 plaque therapy

    International Nuclear Information System (INIS)

    The authors have developed a new inexpensive precious metal alloy plaque for use in customized iodine-125 plaque therapy. Each plaque is formed from two flat circular gold/palladium foils which are used in dental crown work. Using a simple manual mechanism, the two forms are stamped over a customized acrylic die shaped to the dimensions of the tumor base plus a 2-mm margin. Completed plaques consist of a back wall, a 2-mm side wall, and a 1.5-mm wide lip with holes for suture placement. Advantages include: simple construction from inexpensive components, customized shape, and iodine seeds that are readily visible on plane radiographs

  15. Carotid plaque age is a feature of plaque stability inversely related to levels of plasma insulin.

    Directory of Open Access Journals (Sweden)

    Sara Hägg

    Full Text Available BACKGROUND: The stability of atherosclerotic plaques determines the risk for rupture, which may lead to thrombus formation and potentially severe clinical complications such as myocardial infarction and stroke. Although the rate of plaque formation may be important for plaque stability, this process is not well understood. We took advantage of the atmospheric (14C-declination curve (a result of the atomic bomb tests in the 1950s and 1960s to determine the average biological age of carotid plaques. METHODOLOGY/PRINCIPAL FINDING: The cores of carotid plaques were dissected from 29 well-characterized, symptomatic patients with carotid stenosis and analyzed for (14C content by accelerator mass spectrometry. The average plaque age (i.e. formation time was 9.6±3.3 years. All but two plaques had formed within 5-15 years before surgery. Plaque age was not associated with the chronological ages of the patients but was inversely related to plasma insulin levels (p = 0.0014. Most plaques were echo-lucent rather than echo-rich (2.24±0.97, range 1-5. However, plaques in the lowest tercile of plaque age (most recently formed were characterized by further instability with a higher content of lipids and macrophages (67.8±12.4 vs. 50.4±6.2, p = 0.00005; 57.6±26.1 vs. 39.8±25.7, p<0.0005, respectively, less collagen (45.3±6.1 vs. 51.1±9.8, p<0.05, and fewer smooth muscle cells (130±31 vs. 141±21, p<0.05 than plaques in the highest tercile. Microarray analysis of plaques in the lowest tercile also showed increased activity of genes involved in immune responses and oxidative phosphorylation. CONCLUSIONS/SIGNIFICANCE: Our results show, for the first time, that plaque age, as judge by relative incorporation of (14C, can improve our understanding of carotid plaque stability and therefore risk for clinical complications. Our results also suggest that levels of plasma insulin might be involved in determining carotid plaque age.

  16. The pathogenesis of tendinopathy

    DEFF Research Database (Denmark)

    Magnusson, S Peter; Langberg, Henning; Kjær, Michael

    2010-01-01

    , such as tendinopathy, which is characterized by pain during activity, localized tenderness upon palpation, swelling and impaired performance. Tendon histological changes include reduced numbers and rounding of fibroblasts, increased content of proteoglycans, glycosaminoglycans and water...... injury mechanisms, thus implying that one or more 'weak links' are present in the structure. Understanding how tendon tissue adapts to mechanical loading will help to unravel the pathogenesis of tendinopathy....

  17. Pathogenesis of Lassa Fever

    OpenAIRE

    Walker, David H.; Yun, Nadezhda E.

    2012-01-01

    Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesi...

  18. Simian Varicella Virus Pathogenesis

    OpenAIRE

    Mahalingam, Ravi; Messaoudi, Ilhem; Gilden, Don

    2010-01-01

    Because varicella zoster virus (VZV) is an exclusively human pathogen, the development of an animal model is necessary to study pathogenesis, latency, and reactivation. The pathological, virological, and immunological features of simian varicella virus (SVV) infection in nonhuman primates are similar to those of VZV infection in humans. Both natural infection of cynomolgus and African green monkeys as well as intrabronchial inoculation of rhesus macaques with SVV provide the most useful model...

  19. Carotid artery disease : plaque features and vulnerability

    OpenAIRE

    Jashari, Fisnik

    2015-01-01

    Background: Atherosclerosis is an important cause of stroke. Ultrasound offers the convenience of real-time and detailed assessment of carotid plaque features as well as arterial wall thickening and composition. Evaluation of these features is important for determining patients’ risk of suffering vascular events and also contributes to selecting the best treatment strategy. Methods: Using ultrasound data analysis we have determined plaque features in the bifurcation and internal carotid arter...

  20. Functional expression of dental plaque microbiota

    OpenAIRE

    Peterson, Scott N.; Meissner, Tobias; Su, Andrew I.; Snesrud, Erik; Ong, Ana C.; Schork, Nicholas J.; Bretz, Walter A.

    2014-01-01

    Dental caries remains a significant public health problem and is considered pandemic worldwide. The prediction of dental caries based on profiling of microbial species involved in disease and equally important, the identification of species conferring dental health has proven more difficult than anticipated due to high interpersonal and geographical variability of dental plaque microbiota. We have used RNA-Seq to perform global gene expression analysis of dental plaque microbiota derived from...

  1. Oculocutaneous albinism complicated with an ulcerated plaque

    OpenAIRE

    Lokanatha Keshavalu; Priya Kootelu Sundar; Vivekananda; Leena Raveendra; Umashankar Nagaraju; Belliappa Pemmanda Raju

    2013-01-01

    A 32-year-old male with a history of albinism and farmer by occupation presented with an ulcerated plaque on the right wrist. The patient had light eyes, hair, and skin. Physical examination showed extensive photodamage. A skin biopsy specimen from the plaque revealed a well-differentiated squamous-cell carcinoma. Wide surgical excision was done. The most common types of oculocutaneous albinism (OCA), OCA 1 and OCA 2, are autosomal recessive disorders of pigmentation that commonly affect the ...

  2. Regulation of Urease Levels in Microcosm Plaque Dental

    OpenAIRE

    Sissons, C. H.; Wong, L; Cutress, T. W.

    2011-01-01

    The regulation of plaque urease activity by urea, ammonia and arginine was examined using microcosm dental plaques cultured in a multi-plaque ‘artificial mouth‘ from the mixed oral microbiota. The plaques were supplied periodically with sucrose and continuously (3.6 ml/h/plaque) with a much containing medium (BMM) supplemented either with urea at concentrations found in saliva, or with arginine, or ammonia. Urease levels in plaque range from 400 to 1500 nmol NH3/min/mg plaque prot...

  3. Plaque fluid as a bacterial milieu.

    Science.gov (United States)

    Edgar, W M; Higham, S M

    1990-06-01

    Studies of the extracellular, free concentrations of substrates, growth factors, inhibitors, and end-products of metabolism to which the intact plaque microflora is exposed in situ can assist in the understanding of factors controlling plaque pathogenicity. Information is becoming increasingly available from analysis of fluid separated by centrifugation of plaques collected at various intervals after an intra-oral pulse of dietary or experimental substrate, or different procedures or treatments having cariostatic potential. Such analytical results give more information than those obtained by analysis of aqueous or other extracts, because they yield values of substrate concentration representing those occurring at the bacterial cell surface. The largest body of information concerns extracellular levels of acid end-products of sugar catabolism in relation to food quality or sequence, and of amino acids and other products of nitrogen metabolism, in relation to studies of the detailed metabolic events of the Stephan curve, and of the demineralizing effect of the plaque environment. Areas where little information is available and which merit further study include plaque clearance of salivary and other components with anti-caries activity (e.g., antibodies, enzymes, fluorides, cations, other antimicrobials, etc.), and substrate concentrations to determine gradients for diffusion into and out of plaque. PMID:2191982

  4. Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis.

    Science.gov (United States)

    Sheng, Jin G; Price, Donald L; Koliatsos, Vassilis E

    2002-11-15

    We demonstrated previously that amyloid precursor protein (APP) is anterogradely transported from the entorhinal cortex (ERC) to the dentate gyrus via axons of the perforant pathway. In the terminal fields of these inputs, APP undergoes proteolysis to generate C-terminal fragments containing the entire amyloid beta peptide (Abeta) domain. The present study was designed to test the hypothesis that APP derived from ERC neurons is the source of the Abeta peptide deposited in the hippocampal dentate gyrus in Alzheimer's disease (AD) and in transgenic mice with Abeta amyloidosis. We used mice harboring two familial AD-linked genes (human APP Swedish and presenilin1-DeltaE9), in which levels of Abeta (especially Abeta(42)) are elevated, leading to the formation of amyloid plaques, and lesioned the ERC to interrupt the transport of APP from ERC to hippocampus. Our results show that, on the side of ERC lesion, numbers of APP-immunoreactive dystrophic neurites and Abeta burden were significantly reduced by approximately 40 and 45%, respectively, in the dentate gyrus compared with the contralateral side. Reductions in APP and Abeta were more substantial in the molecular layer of the dentate, i.e., a region that contains the ERC terminals, and were associated with a parallel decrease in total APP and Abeta measured by Western blot and ProteinChip immunoassays. Silver and thioflavine staining confirmed the reduction of amyloid plaques on the side of deafferentation. These results are consistent with the hypothesis that ERC may be the primary source of amyloidogenic Abeta in the dentate gyrus, and they suggest an important role of corticocortical and corticolimbic forward connections in determining patterns of amyloid deposition in AD. PMID:12427835

  5. Amyloid Goiter Secondary to Ulcerative Colitis

    Directory of Open Access Journals (Sweden)

    Bunyamin Aydin

    2016-01-01

    Full Text Available Diffuse amyloid goiter (AG is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn’s disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis.

  6. Amyloid Goiter Secondary to Ulcerative Colitis.

    Science.gov (United States)

    Aydin, Bunyamin; Koca, Yavuz Savas; Koca, Tugba; Yildiz, Ihsan; Gerek Celikden, Sevda; Ciris, Metin

    2016-01-01

    Diffuse amyloid goiter (AG) is an entity characterized by the deposition of amyloid in the thyroid gland. AG may be associated with either primary or secondary amyloidosis. Secondary amyloidosis is rarely caused by inflammatory bowel diseases. Secondary amyloidosis is relatively more common in the patients with Crohn's disease, whereas it is highly rare in patients with ulcerative colitis. Diffuse amyloid goiter caused by ulcerative colitis is also a rare condition. In the presence of amyloid in the thyroid gland, medullary thyroid cancer should be kept in mind in the differential diagnosis. Imaging techniques and biochemical tests are not very helpful in the diagnosis of secondary amyloid goiter and the definitive diagnosis is established based on the histopathologic analysis and histochemical staining techniques. In this report, we present a 35-year-old male patient with diffuse amyloid goiter caused by secondary amyloidosis associated with ulcerative colitis. PMID:27051538

  7. DNA aptamers detecting generic amyloid epitopes

    OpenAIRE

    Mitkevich, Olga V.; Kochneva-Pervukhova, Natalia V; Surina, Elizaveta R.; Benevolensky, Sergei V.; Kushnirov, Vitaly V.; Ter-Avanesyan, Michael D.

    2012-01-01

    Amyloids are fibrillar protein aggregates resulting from non-covalent autocatalytic polymerization of various structurally and functionally unrelated proteins. Previously we have selected DNA aptamers, which bind specifically to the in vitro assembled amyloid fibrils of the yeast prionogenic protein Sup35. Here we show that such DNA aptamers can be used to detect SDS-insoluble amyloid aggregates of the Sup35 protein, and of some other amyloidogenic proteins, including mouse PrP, formed in yea...

  8. Amyloid myopathy: a diagnostic challenge

    Directory of Open Access Journals (Sweden)

    Heli Tuomaala

    2009-08-01

    Full Text Available Amyloid myopathy (AM is a rare manifestation of primary systemic amyloidosis (AL. Like inflammatory myopathies, it presents with proximal muscle weakness and an increased creatine kinase level. We describe a case of AL with severe, rapidly progressive myopathy as the initial symptom. The clinical manifestation and muscle biopsy were suggestive of inclusion body myositis. AM was not suspected until amyloidosis was seen in the gastric mucosal biopsy. The muscle biopsy was then re-examined more specifically, and Congo red staining eventually showed vascular and interstitial amyloid accumulation, which led to a diagnosis of AM. The present case illustrates the fact that the clinical picture of AM can mimic that of inclusion body myositis.

  9. Towards a Pharmacophore for Amyloid

    Science.gov (United States)

    Landau, Meytal; Sawaya, Michael R.; Faull, Kym F.; Laganowsky, Arthur; Jiang, Lin; Sievers, Stuart A.; Liu, Jie; Barrio, Jorge R.; Eisenberg, David

    2011-01-01

    Diagnosing and treating Alzheimer's and other diseases associated with amyloid fibers remains a great challenge despite intensive research. To aid in this effort, we present atomic structures of fiber-forming segments of proteins involved in Alzheimer's disease in complex with small molecule binders, determined by X-ray microcrystallography. The fiber-like complexes consist of pairs of β-sheets, with small molecules binding between the sheets, roughly parallel to the fiber axis. The structures suggest that apolar molecules drift along the fiber, consistent with the observation of nonspecific binding to a variety of amyloid proteins. In contrast, negatively charged orange-G binds specifically to lysine side chains of adjacent sheets. These structures provide molecular frameworks for the design of diagnostics and drugs for protein aggregation diseases. PMID:21695112

  10. In vivo and in vitro evidence that Tc-99m-HYNIC-interleukin-2 is able to detect T lymphocytes in vulnerable atherosclerotic plaques of the carotid artery

    NARCIS (Netherlands)

    Glaudemans, Andor W. J. M.; Bonanno, Elena; Galli, Filippo; Zeebregts, Clark J.; de Vries, Erik; Koole, Michel; Luurtsema, Gert; Boersma, Hendrikus H.; Taurino, Maurizio; Slart, Riemer H. J. A.; Signore, Alberto

    2014-01-01

    Purpose Recent advances in basic science have established that inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Inflammatory cells are thought to be responsible for the transformation of a stable plaque into a vulnerable one. Lymphocytes constitute at least 20 % of infiltrat

  11. A theranostic agent for in vivo near-infrared imaging of β-amyloid species and inhibition of β-amyloid aggregation.

    Science.gov (United States)

    Li, Yinhui; Xu, Di; Ho, See-Lok; Li, Hung-Wing; Yang, Ronghua; Wong, Man Shing

    2016-07-01

    Amyloid-β (Aβ) peptide as one of the main components of senile plaques is closely related to the onset and progression of incurable Alzheimer's disease (AD). Numerous efforts have been devoted to develop probes for Aβ species/plaque imaging for AD diagnostics and to develop aggregation inhibitors preventing formation of toxic soluble oligomeric Aβ for therapeutics. Herein, for the first time, a series of novel charged molecules, which can simultaneously perform near infra-red in vivo imaging of Aβ species/plaques in animal model and inhibition of self-aggregation of Aβ monomer from forming toxic oligomers, are reported. Among them, DBA-SLOH showed excellent blood-brain barrier (BBB) permeability and biocompatibility due to the incorporation of lipophilic alkyl chains with moderate length into the charged skeleton. Importantly, DBA-SLOH was found to have a high binding affinity toward Aβ species exhibiting a dramatic fluorescence enhancement upon interacting with Aβ species. Despite a weaker binding with Aβ monomers as compared to Aβ aggregates, DBA-SLOH could effectively prevent the Aβ1-40 and Aβ1-42 peptides from self-aggregation and forming toxic oligomers. This multifunctional fluorescent molecule shows promising potential as a theranostic agent for the diagnosis and therapy of AD. PMID:27107167

  12. Antibody-conjugated, dual-modal, near-infrared fluorescent iron oxide nanoparticles for antiamyloidgenic activity and specific detection of amyloid-β fibrils

    Directory of Open Access Journals (Sweden)

    Skaat H

    2013-10-01

    Full Text Available Hadas Skaat,1 Enav Corem-Slakmon,1 Igor Grinberg,1 David Last,2 David Goez,2 Yael Mardor,2,3 Shlomo Margel1 1Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Ramat-Gan, Israel; 2Advanced Technology Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel; 3Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel Abstract: Amyloid-β (Aβ peptide is the main fibrillar component of plaque deposits found in brains affected by Alzheimer's disease (AD and is related to the pathogenesis of AD. Passive anti-Aβ immunotherapy has emerged as a promising approach for the therapy of AD, based on the administration of specific anti-Aβ monoclonal antibodies (aAβmAbs to delay Aβ aggregation in the brain. However, the main disadvantage of this approach is the required readministration of the aAβmAbs at frequent intervals. There are only a few reports describing in vitro study for the immobilization of aAβmAbs to nanoparticles as potential targeting agents of Aβ aggregates. In this article, we report the immobilization of the aAβmAb clone BAM10 to near-infrared fluorescent maghemite nanoparticles for the inhibition of Aβ40 fibrillation kinetics and the specific detection of Aβ40 fibrils. The BAM10-conjugated iron oxide nanoparticles were well-characterized, including their immunogold labeling and cytotoxic effect on PC-12 (pheochromocytoma cell line. Indeed, these antibody-conjugated nanoparticles significantly inhibit the Aβ40 fibrillation kinetics compared with the same concentration, or even five times higher, of the free BAM10. This inhibitory effect was confirmed by different assays such as the photo-induced crosslinking of unmodified proteins combined with sodium dodecyl sulfate–polyacrylamide gel electrophoresis. A cell viability assay also confirmed that these antibody-conjugated nanoparticles significantly reduced the Aβ40-induced cytotoxicity to PC-12 cells. Furthermore, the selective

  13. Molecular Pathogenesis of Spondyloarthritis

    DEFF Research Database (Denmark)

    Carlsen, Thomas Gelsing

    This dissertation includes a presentation of knowledge on the molecular pathogenesis of spondyloarthritis achieved through a PhD programme at Aalborg University from 1.12.2011 - 1.12.2014. Work was carried out in the Laboratory of Medical Mass Spectrometry, headed by: Professor Svend Birkelund...... Associate Professor Allan Stensballe The output of this PhD programme, besides from this dissertation, includes 5 published papers, 30 ECTS PhD courses, oral presentations of posters in national and international research environment and a short-term scholarship at the La Jolla Institute for Allergy and...

  14. 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

  15. Transcranial laser therapy alters amyloid precursor protein processing and improves mitochondrial function in a mouse model of Alzheimer's disease

    Science.gov (United States)

    McCarthy, Thomas; Yu, Jin; El-Amouri, Salim; Gattoni-Celli, Sebastiano; Richieri, Steve; De Taboada, Luis; Streeter, Jackson; Kindy, Mark S.

    2011-03-01

    Transcranial laser therapy (TLT) using a near-infrared energy laser system was tested in the 2x Tg amyloid precursor protein (APP) mouse model of Alzheimer's Disease (AD). TLT was administered 3 times/week at escalating doses, starting at 3 months of age, and was compared to a control group which received no laser treatment. Treatment sessions were continued for a total of six months. The brains were examined for amyloid plaque burden, Aβ peptides (Aβ1-40 and Aβ1-42 ), APP cleavage products (sAPPα, CTFβ) and mitochondrial activity. Administration of TLT was associated with a significant, dose-dependent reduction in amyloid load as indicated by the numbers of Aβ plaques. Levels of Aβ1-40 and Aβ1-42 levels were likewise reduced in a dose-dependent fashion. All TLT doses produced an increase in brain sAPPα and a decrease in CTFβ levels consistent with an increase in α-secretase activity and a decrease in β-secretase activity. In addition, TLT increased ATP levels and oxygen utilization in treated animals suggesting improved mitochondrial function. These studies suggest that TLT is a potential candidate for treatment of AD.

  16. BIIB042, a novel γ-secretase modulator, reduces amyloidogenic Aβ isoforms in primates and rodents and plaque pathology in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Scannevin, Robert H; Chollate, Sowmya; Brennan, Melanie S; Snodgrass-Belt, Pamela A; Peng, Hairuo; Xu, Lin; Jung, Mi-Young; Bussiere, Thierry; Arastu, Mahin F; Talreja, Tina; Xin, Zhili; Dunstan, Robert W; Fahrer, Diana; Rohde, Ellen; Dunah, Anthone W; Wang, Joy; Kumaravel, Gnanasambandam; Taveras, Arthur G; Moore Arnold, H; Rhodes, Kenneth J

    2016-04-01

    Reducing the production of larger aggregation-prone amyloid β-peptides (Aβ) remains an untested therapeutic approach for reducing the appearance and growth of Aβ plaques in the brain, which are a hallmark pathological feature of Alzheimer's disease. γ-Secretase modulators (GSMs) are therapeutics that impact γ-secretase-dependent cleavage of amyloid precursor protein to promote the production of shorter Aβ peptides that are less prone to aggregation and plaque deposition. This is accomplished without inhibiting overall γ-secretase function and cleavage of other substrates, which is believed to be a source of deleterious side effects. Here, we report the pharmacokinetic and pharmacodynamic properties of BIIB042, a novel bioavailable and brain-penetrant GSM. In cell-based assays, BIIB042 reduced the levels of Aβ42, increased the levels of Aβ38 and had little effect on the levels of Aβ40, the most abundant Aβ species. Similar pharmacodynamic properties were confirmed in the central nervous system and in plasma of mice and rats, and also in plasma of cynomolgus monkeys after a single oral dose of BIIB042. BIIB042 reduced Aβ42 levels and Aβ plaque burden in Tg2576 mice, which overexpress human amyloid precursor protein and serve as a model system for Alzheimer's disease. BIIB042 did not inhibit cleavage of other γ-secretase substrates in cell-based and in vivo signaling and cleavage assays. The pharmacodynamic effects of lowering Aβ42 in the central nervous system coupled with demonstrated efficacy in reducing plaque pathology suggests modulation of γ-secretase, with molecules like BIIB042, is a compelling therapeutic approach for the treatment of Alzheimer's disease. PMID:26690893

  17. DECT evaluation of noncalcified coronary artery plaque

    Energy Technology Data Exchange (ETDEWEB)

    Ravanfar Haghighi, Rezvan [Medical Imaging Research Center and Colorectal Research Center, Shiraz University of Medical Science, Shiraz 719 363 5899 (Iran, Islamic Republic of); Chatterjee, S. [BGVS Chemical Engineering Building (Old), Indian Institute of Science, Bangalore 560012 (India); Tabin, Milo; Singh, Rishi P.; Sharma, Munish; Krishna, Karthik [Department of Forensic Medicine, All India Institute of Medical Sciences, New Delhi 110029 (India); Sharma, Sanjiv; Jagia, Priya [Department of Cardiac-Radiology, All India Institute of Medical Sciences, New Delhi 110029 (India); Ray, Ruma; Arava, Sudhir [Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029 (India); Yadav, Rakesh [Department of Cardiology, All India Institute of Medical Sciences, New Delhi 110029 (India); Vani, V. C. [Department of Instrumentation and Applied Physics, Indian Institute of Science, Bangalore 560012 (India); Lakshmi, R.; Kumar, Pratik, E-mail: drpratikkumar@gmail.com [Department of Cardiac-Biochemistry, All India Institute of Medical Sciences, New Delhi 110029 (India); Mandal, Susama R. [Department of Medical Physics Unit IRCH, All India Institute of Medical Sciences, New Delhi 110029 (India)

    2015-10-15

    Purpose: Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (ρ{sub e}) and the effective atomic number (Z{sub eff}) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. Methods: For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (ρ{sub e}, Z{sub eff}) lie in the range of (2.65 × 10{sup 23} ≤ ρ{sub e} ≤ 3.64 × 10{sup 23}/cm{sup 3}) and (6.80 ≤ Z{sub eff} ≤ 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V{sub 1}) and HU(V{sub 2}), with V{sub 1},V{sub 2} = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (ρ{sub e}, Z{sub eff}) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (ρ{sub e}, Z{sub eff}) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. Results: The authors find that the calibration gives ρ{sub e} with an accuracy of ±3.5% while Z{sub eff} is found within ±1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques

  18. Pathogenesis of Arrhythmogenic Cardiomyopathy.

    Science.gov (United States)

    Asimaki, Angeliki; Kleber, Andre G; Saffitz, Jeffrey E

    2015-11-01

    Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease. It is characterized by frequent ventricular arrhythmias and increased risk of sudden cardiac death typically arising as an early manifestation before the onset of significant myocardial remodelling. Myocardial degeneration, often confined to the right ventricular free wall, with replacement by fibrofatty scar tissue, develops in many patients. ACM is a familial disease but genetic penetrance can be low and disease expression is highly variable. Inflammation might promote disease progression. It also appears that exercise increases disease penetrance and accelerates its development. More than 60% of probands harbour mutations in genes that encode desmosomal proteins, which has raised the possibility that defective cell-cell adhesion might play a role in disease pathogenesis. Recent advances have implicated changes in the canonical wingless-type mouse mammary tumour virus integration site (Wnt)/β-catenin and Hippo signalling pathways and defects in forwarding trafficking of ion channels and other proteins to the intercalated disk in cardiac myocytes. In this review we summarize the current understanding of the pathogenesis of ACM and highlight future research directions. PMID:26199027

  19. Inhibition of histone deacetylase 2 mitigates profibrotic TGF-β1 responses in fibroblasts derived from Peyronie's plaque

    OpenAIRE

    Ryu, Ji-Kan; Kim, Woo-Jean; Choi, Min-Ji; Park, Jin-Mi; Song, Kang-Moon; Kwon, Mi-Hye; Das, Nando-Dulal; Kwon, Ki-Dong; Batbold, Dulguun; Yin, Guo-Nan; Suh, Jun-Kyu

    2013-01-01

    Epigenetic modifications, such as histone acetylation/deacetylation, have been shown to play a role in the pathogenesis of fibrotic disease. Peyronie's disease (PD) is a localized fibrotic process of the tunica albuginea, which leads to penile deformity. This study was undertaken to determine the anti-fibrotic effect of small interfering RNA (siRNA)-mediated silencing of histone deacetylase 2 (HDAC2) in primary fibroblasts derived from human PD plaque. PD fibroblasts were pre-treated with HDA...

  20. Functional Expression of Dental Plaque Microbiota

    Directory of Open Access Journals (Sweden)

    Scott Norman Peterson

    2014-08-01

    Full Text Available Dental caries remains a significant public health problem and is considered pandemic worldwide. The prediction of dental caries based on profiling of microbial species involved in disease and equally important, the identification of species conferring dental health has proven more difficult than anticipated due to high interpersonal and geographical variability of dental plaque microbiota. We have used RNA-Seq to perform global gene expression analysis of dental plaque microbiota derived from 19 twin pairs that were either concordant (caries-active or caries-free or discordant for dental caries. The transcription profiling allowed us to define a functional core microbiota consisting of nearly 60 species. Similarities in gene expression patterns allowed a preliminary assessment of the relative contribution of human genetics, environmental factors and caries phenotype on the microbiota’s transcriptome. Correlation analysis of transcription allowed the identification of numerous functional networks, suggesting that inter-personal environmental variables may co-select for groups of genera and species. Analysis of functional role categories allowed the identification of dominant functions expressed by dental plaque biofilm communities, that highlight the biochemical priorities of dental plaque microbes to metabolize diverse sugars and cope with the acid and oxidative stress resulting from sugar fermentation. The wealth of data generated by deep sequencing of expressed transcripts enables a greatly expanded perspective concerning the functional expression of dental plaque microbiota.

  1. Hyperspectral imaging of atherosclerotic plaques in vitro

    Science.gov (United States)

    Larsen, Eivind L. P.; Randeberg, Lise L.; Olstad, Elisabeth; Haugen, Olav A.; Aksnes, Astrid; Svaasand, Lars O.

    2011-02-01

    Vulnerable plaques constitute a risk for serious heart problems, and are difficult to identify using existing methods. Hyperspectral imaging combines spectral- and spatial information, providing new possibilities for precise optical characterization of atherosclerotic lesions. Hyperspectral data were collected from excised aorta samples (n = 11) using both white-light and ultraviolet illumination. Single lesions (n = 42) were chosen for further investigation, and classified according to histological findings. The corresponding hyperspectral images were characterized using statistical image analysis tools (minimum noise fraction, K-means clustering, principal component analysis) and evaluation of reflectance/fluorescence spectra. Image analysis combined with histology revealed the complexity and heterogeneity of aortic plaques. Plaque features such as lipids and calcifications could be identified from the hyperspectral images. Most of the advanced lesions had a central region surrounded by an outer rim or shoulder-region of the plaque, which is considered a weak spot in vulnerable lesions. These features could be identified in both the white-light and fluorescence data. Hyperspectral imaging was shown to be a promising tool for detection and characterization of advanced atherosclerotic plaques in vitro. Hyperspectral imaging provides more diagnostic information about the heterogeneity of the lesions than conventional single point spectroscopic measurements.

  2. From Lipid Retention to Immune-Mediate Inflammation and Associated Angiogenesis in the Pathogenesis of Atherosclerosis.

    Science.gov (United States)

    Usman, Ammara; Ribatti, Domenico; Sadat, Umar; Gillard, Jonathan H

    2015-08-26

    Atherosclerosis is a leading cause of mortality and long-term morbidity worldwide. It is a lipoprotein-driven disease that leads to plaque formation at focal areas in the arterial blood vessels through intimal inflammation, necrosis, fibrosis, and calcification. Adventitial and intimal angiogenesis contributes to the progression of intimal hyperplasia and the development of a necrotic core. The volatile nature of an atheromatous plaque is responsible for approximately 60% of symptomatic carotid artery diseases and about 75% of acute coronary events. In this review the pathogenesis of atherosclerosis is discussed from the initial step of lipid retention to advanced stages of immune-mediate inflammation and associated angiogenesis. Mechanisms of plaque rupture are also discussed. PMID:26156748

  3. The amyloid in familial amyloid cardiomyopathy of Danish origin is related to pre-albumin.

    Science.gov (United States)

    Husby, G; Ranløv, P J; Sletten, K; Marhaug, G

    1985-04-01

    Amyloid obtained from the myocardium of a patient (Han) with familial amyloid cardiomyopathy of Danish origin was studied. Gel filtration and electrophoresis of purified and denatured amyloid fibrils Han revealed various fractions ranging in mol. wt from 40,000 to 8,000 daltons. Amyloid Han and fractions reacted with an antiserum against amyloid Han showing a reaction of identity with each other; partial identity between Han and human pre-albumin was observed, while no reaction was seen with AA or AL proteins. Cardiac tissue sections from Han showed reactivity with antisera to amyloid Han, pre-albumin and protein AP, but not with anti-AA or anti-AL in indirect immunofluorescence. Amino acid composition and sequence studies of a protein fraction of amyloid Han with mol. wt 15,000 daltons confirmed the structural relationship with pre-albumin. PMID:3924450

  4. Effect of delmopinol hydrochloride mouthrinse on plaque formation and gingivitis in "rapid" and "slow" plaque formers.

    Science.gov (United States)

    Zee, K; Rundegren, J; Attström, R

    1997-07-01

    The aim of the present study was to investigate differences in the plaque and gingivitis inhibiting effect of delmopinol rinsing between "rapid" and "slow" plaque formers. 23 subjects (12 "rapid" and 11 "slow" plaque formers) were selected from 71 healthy young adults. The selection was based on the plaque index on the buccal surfaces of all premolars and 1st molars after 3-days without plaque control. The 23 subjects were randomly assigned into 3 groups with different mouthrinses, i.e., 0.1% delmopinol, 0.2% delmopinol, and placebo. The study was double-blind with parallel design between the "rapid" and "slow" plaque formers and cross-over design between 2 active periods and a placebo period. Each rinsing period lasted for 5 days. During the 3 test periods, the subjects refrained from all oral hygiene and rinsed 2x daily with either one of the 3 solutions. Gingival crevicular fluid (GCF) was collected from buccal surfaces of upper canines and premolars and bleeding on probing (BOP) recorded at 6 sites around each tooth before and after each test period. Plaque assessment, including plaque index (PI) and standardized color slides for planimetric analyses obtained from the canines and premolars, were only recorded after each test period. Results showed that the mean PI and planimetry values for both the "rapid" and "slow" plaque formers were lower than the placebo, for either the 0.1% or the 0.2% delmopinol mouthrinse. The differences between the" rapid" and "slow" plaque formers were not statistically significant. There was a small reduction in BOP in both groups for the delmopinol periods, as against a slight increase in the placebo period; the difference between the placebo group and the 2 groups of plaque formers was not statistically significant (p>0.6 for both 0.1% and 0.2% delmopinol). Results suggested that both 0.1% and 0.2% delmopinol reduce plaque formation and gingivitis to a similar extent in subjects with extreme rates of plaque formation. PMID:9226389

  5. Evidence for Inhibition of Lysozyme Amyloid Fibrillization by Peptide Fragments from Human Lysozyme: A Combined Spectroscopy, Microscopy, and Docking Study.

    Science.gov (United States)

    Kar, Rajiv K; Gazova, Zuzana; Bednarikova, Zuzana; Mroue, Kamal H; Ghosh, Anirban; Zhang, Ruiyan; Ulicna, Katarina; Siebert, Hans-Christian; Nifantiev, Nikolay E; Bhunia, Anirban

    2016-06-13

    Degenerative diseases, such as Alzheimer's and prion diseases, as well as type II diabetes, have a pathogenesis associated with protein misfolding, which routes with amyloid formation. Recent strategies for designing small-molecule and polypeptide antiamyloid inhibitors are mainly based on mature fibril structures containing cross β-sheet structures. In the present study, we have tackled the hypothesis that the rational design of antiamyloid agents that can target native proteins might offer advantageous prospect to design effective therapeutics. Lysozyme amyloid fibrillization was treated with three different peptide fragments derived from lysozyme protein sequence R(107)-R(115). Using low-resolution spectroscopic, high-resolution NMR, and STD NMR-restrained docking methods such as HADDOCK, we have found that these peptide fragments have the capability to affect lysozyme fibril formation. The present study implicates the prospect that these peptides can also be tested against other amyloid-prone proteins to develop novel therapeutic agents. PMID:27116396

  6. Potential role of ixekizumab in the treatment of moderate-to-severe plaque psoriasis

    Directory of Open Access Journals (Sweden)

    Ren V

    2013-03-01

    Full Text Available Vicky Ren,1 Harry Dao Jr2 1Baylor College of Medicine , School of Medicine, 2Department of Dermatology, Baylor College of Medicine Houston, TX, USA Background: Psoriasis is a debilitating autoimmune skin disease that affects 2%–3% of the world's population. Patients with moderate-to-severe plaque psoriasis suffer from a decreased quality of life as well as comorbidities. Newer biological agents have been shown to be more effective than traditional therapies. In this article, we assess the potential role of ixekizumab, an anti-interleukin (IL-17 antibody, in treating moderate-to-severe plaque psoriasis. Method: We reviewed PubMed for articles regarding ixekizumab and the epidemiology and management of plaque psoriasis. Results: In a Phase I clinical trial, treatment with ixekizumab resulted in both clinical and histopathologic improvement of psoriasis, which suggests that IL-17 may be a key driver in the pathogenesis of psoriasis. In a Phase II clinical trial, treatment with ixekizumab resulted in rapid clinical improvement of psoriasis, which lends further support to its role as an effective treatment for patients with chronic moderate-to-severe plaque psoriasis. Reductions in Psoriasis Area and Severity Index (PASI score are comparable to those associated with currently marketed biologics. Conclusion: Literature concerning the effects of ixekizumab on chronic moderate-to-severe plaque psoriasis is currently limited to two clinical trials. Results suggest that ixekizumab shows great therapeutic promise. However, more large-scale and long-term trials are needed to establish safety and efficacy. Keywords: IL-17, PASI, adalimumab, etanercept, infliximab, ustekinumab, biologics

  7. Amyloid-β-Anti-Amyloid-β Complex Structure Reveals an Extended Conformation in the Immunodominant B-Cell Epitope

    Energy Technology Data Exchange (ETDEWEB)

    Miles, Luke A; Wun, Kwok S; Crespi, Gabriela A.N.; Fodero-Tavoletti, Michelle T; Galatis, Denise; Bagley, Christopher J; Beyreuther, Konrad; Masters, Colin L; Cappai, Roberto; McKinstry, William J; Barnham, Kevin J; Parker, Michael W [SVIMR-A; (Hanson); (Heidelberg); (Melbourne)

    2012-04-17

    Alzheimer's disease (AD) is the most common form of dementia. Amyloid-β (Aβ) peptide, generated by proteolytic cleavage of the amyloid precursor protein, is central to AD pathogenesis. Most pharmaceutical activity in AD research has focused on Aβ, its generation and clearance from the brain. In particular, there is much interest in immunotherapy approaches with a number of anti-Aβ antibodies in clinical trials. We have developed a monoclonal antibody, called WO2, which recognises the Aβ peptide. To this end, we have determined the three-dimensional structure, to near atomic resolution, of both the antibody and the complex with its antigen, the Aβ peptide. The structures reveal the molecular basis for WO2 recognition and binding of Aβ. The Aβ peptide adopts an extended, coil-like conformation across its major immunodominant B-cell epitope between residues 2 and 8. We have also studied the antibody-bound Aβ peptide in the presence of metals known to affect its aggregation state and show that WO2 inhibits these interactions. Thus, antibodies that target the N-terminal region of Aβ, such as WO2, hold promise for therapeutic development.

  8. Statistical segmentation of carotid plaque neovascularization

    Science.gov (United States)

    Akkus, Zeynettin; Bosch, Johan G.; Sánchez-Ferrero, Gonzalo V.; Carvalho, Diego D. B.; Renaud, Guillaume; van den Oord, Stijn C. H.; ten Kate, Gerrit L.; Schinkel, Arend F. L.; de Jong, Nico; van der Steen, Antonius F. W.

    2013-03-01

    In several studies, intraplaque neovascularization (IPN) has been linked with plaque vulnerability. The recent development of contrast enhanced ultrasound enables IPN detection, but an accurate quantification of IPN is a big challenge due to noise, motion, subtle contrast response, blooming of contrast and artifacts. We present an algorithm that automatically estimates the location and amount of contrast within the plaque over time. Plaque pixels are initially labeled through an iterative expectation-maximization (EM) algorithm. The used algorithm avoids several drawbacks of standard EM. It is capable of selecting the best number of components in an unsupervised way, based on a minimum message length criterion. Next, neighborhood information using a 5×5 kernel and spatiotemporal behavior are combined with the known characteristics of contrast spots in order to group components, identify artifacts and finalize the classification. Image sequences are divided into 3-seconds subgroups. A pixel is relabeled as an artifact if it is labeled as contrast for more than 1.5 seconds in at least two subgroups. For 10 plaques, automated segmentation results were validated with manual segmentation of contrast in 10 frames per clip. Average Dice index and area ratio were 0.73+/-0.1 (mean+/-SD) and 98.5+/-29.6 (%) respectively. Next, 45 atherosclerotic plaques were analyzed. Time integrated IPN surface area was calculated. Average area of IPN was 3.73+/-3.51 mm2. Average area of 45 plaques was 11.6+/-8.6 mm2. This method based on EM contrast segmentation provides a new way of IPN quantification.

  9. Cobalt60 plaques in recurrent retinoblastoma

    International Nuclear Information System (INIS)

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 x 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications

  10. Cobalt60 plaques in recurrent retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fass, D.; McCormick, B.; Abramson, D.; Ellsworth, R. (Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, NY, NY (USA))

    1991-08-01

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 {times} 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications.

  11. Membrane Incorporation, Channel Formation, and Disruption of Calcium Homeostasis by Alzheimer's β-Amyloid Protein

    Directory of Open Access Journals (Sweden)

    Masahiro Kawahara

    2011-01-01

    Full Text Available Oligomerization, conformational changes, and the consequent neurodegeneration of Alzheimer's β-amyloid protein (AβP play crucial roles in the pathogenesis of Alzheimer's disease (AD. Mounting evidence suggests that oligomeric AβPs cause the disruption of calcium homeostasis, eventually leading to neuronal death. We have demonstrated that oligomeric AβPs directly incorporate into neuronal membranes, form cation-sensitive ion channels (“amyloid channels”, and cause the disruption of calcium homeostasis via the amyloid channels. Other disease-related amyloidogenic proteins, such as prion protein in prion diseases or α-synuclein in dementia with Lewy bodies, exhibit similarities in the incorporation into membranes and the formation of calcium-permeable channels. Here, based on our experimental results and those of numerous other studies, we review the current understanding of the direct binding of AβP into membrane surfaces and the formation of calcium-permeable channels. The implication of composition of membrane lipids and the possible development of new drugs by influencing membrane properties and attenuating amyloid channels for the treatment and prevention of AD is also discussed.

  12. Tissue distribution of amyloid deposits in Abyssinian cats with familial amyloidosis.

    Science.gov (United States)

    DiBartola, S P; Tarr, M J; Benson, M D

    1986-07-01

    The tissue distribution of amyloid deposits was studied in 15 related Abyssinian cats with familial amyloidosis. There was interstitial medullary amyloidosis in the kidneys of all 15 cats but only 11 had detectable glomerular involvement. The thyroid glands, stomach and colon were affected in all cats examined. Most of the cats also had amyloid deposits in the small intestine, spleen, heart, adrenals, pancreas, liver, lymph nodes and bladder. In 50 per cent or fewer of the cats examined, there was involvement of the parathyroids, lung and gonads. The central nervous system was not involved in any of the 3 cats evaluated. In 8 of the cats, no concurrent inflammatory disease could be detected. The tissue distribution of amyloid deposits resembled that found in other breeds of domestic cats with systemic amyloidosis. Despite the wide tissue distribution of amyloid deposits, clinical signs were related to renal amyloidosis. Familial amyloidosis in the Abyssinian cat may represent a valuable spontaneous animal model for the study of Familial Mediterranean Fever in man and the pathogenesis of reactive amyloidosis in general. PMID:3734172

  13. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain.

    Science.gov (United States)

    Cox, Paul Alan; Davis, David A; Mash, Deborah C; Metcalf, James S; Banack, Sandra Anne

    2016-01-27

    Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk. PMID:26791617

  14. Amyloid β-Protein as a Substrate Interacts with Extracellular Matrix to Promote Neurite Outgrowth

    Science.gov (United States)

    Koo, Edward H.; Park, Lisa; Selkoe, Dennis J.

    1993-05-01

    Progressive deposition of amyloid β-protein (Aβ) in brain parenchyma and blood vessels is a characteristic feature of Alzheimer disease. Recent evidence suggests that addition of solubilized synthetic Aβ to medium may produce toxic or trophic effects on cultured hippocampal neurons. Because soluble Aβ may not accumulate in significant quantities in brain, we asked whether immobilized Aβ peptide as a substrate alters neurite outgrowth from cultured rat peripheral sensory neurons. This paradigm may closely mimic the conditions in Alzheimer disease brain tissue, in which neurites contact insoluble, extracellular aggregates of β-amyloid. We detected no detrimental effects of Aβ substrate on neurite outgrowth. Rather, Aβ in combination with low doses of laminin or fibronectin enhanced neurite out-growth from these neuronal explants. Our results suggest that insoluble Aβ in the cerebral neuropil may serve as a neurite-promoting matrix, perhaps explaining the apparent regenerative response of neurites observed around amyloid plaques in Alzheimer disease. Moreover, in concert with the recent discovery of Aβ production by cultured neurons, our data suggest that Aβ plays a normal physiological role in brain by complexing with the extracellular matrix.

  15. Pathogenesis of Lassa fever.

    Science.gov (United States)

    Yun, Nadezhda E; Walker, David H

    2012-10-01

    Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host's immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents. PMID:23202452

  16. Pathogenesis of Lassa Fever

    Directory of Open Access Journals (Sweden)

    David H. Walker

    2012-10-01

    Full Text Available Lassa virus, an Old World arenavirus (family Arenaviridae, is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host’s immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents.

  17. Pathogenesis of Lassa Fever

    Science.gov (United States)

    Yun, Nadezhda E.; Walker, David H.

    2012-01-01

    Lassa virus, an Old World arenavirus (family Arenaviridae), is the etiological agent of Lassa fever, a severe human disease that is reported in more than 100,000 patients annually in the endemic regions of West Africa with mortality rates for hospitalized patients varying between 5-10%. Currently, there are no approved vaccines against Lassa fever for use in humans. Here, we review the published literature on the life cycle of Lassa virus with the specific focus put on Lassa fever pathogenesis in humans and relevant animal models. Advancing knowledge significantly improves our understanding of Lassa virus biology, as well as of the mechanisms that allow the virus to evade the host’s immune system. However, further investigations are required in order to design improved diagnostic tools, an effective vaccine, and therapeutic agents. PMID:23202452

  18. MR Imaging of Coronary Arteries and Plaques.

    Science.gov (United States)

    Dweck, Marc R; Puntman, Valentina; Vesey, Alex T; Fayad, Zahi A; Nagel, Eike

    2016-03-01

    Cardiac magnetic resonance offers the promise of radiation-free imaging of the coronary arteries, providing information with respect to luminal stenosis, plaque burden, high-risk plaque characteristics, and disease activity. In combination, this would provide a comprehensive, individualized assessment of coronary atherosclerosis that could be used to improve patient risk stratification and to guide treatment. However, the technical challenges involved with delivering upon this promise are considerable, requiring sophisticated approaches to both data acquisition and post-processing. In this review, we describe the current status of this technology, its capabilities, its limitations, and what will be required in the future to translate this technology into routine clinical practice. PMID:26965732

  19. Fluoride bioavailability in saliva and plaque

    OpenAIRE

    Naumova Ella A; Kuehnl Phillip; Hertenstein Philipp; Markovic Ljubisa; Jordan Rainer A; Gaengler Peter; Arnold Wolfgang H

    2012-01-01

    Abstract Background Different fluoride formulations may have different effects on caries prevention. It was the aim of this clinical study to assess the fluoride content, provided by NaF compared to amine fluoride, in saliva and plaque. Methods Eight trained volunteers brushed their teeth in the morning for 3 minutes with either NaF or amine fluoride, and saliva and 3-day-plaque-regrowth was collected at 5 time intervals during 6 hours after tooth brushing. The amount of collected saliva and ...

  20. DENTAL PLAQUE – CLASSIFICATION, FORMATION, AND IDENTIFICATION

    OpenAIRE

    Viorica CHETRUS; I.R. ION

    2013-01-01

    The aim of this study was to present the most effective and easiest ways to diagnoze dental plaque, and to distin‐ guish some modern and effective methods for its removal. Materials and method. The study was performed on 34 patients aged between 19‐42 years. For dental plaque detection, the (QHT) index in two different ‐ initial and final – stages, was used. For the removal of sub‐gingival and supra‐gingival soft and hard deposits, scaling was used, as well as AIR FLOW professional brushing f...

  1. Pathogenesis of nasal polyposis.

    Science.gov (United States)

    Hulse, K E; Stevens, W W; Tan, B K; Schleimer, R P

    2015-02-01

    Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world-wide and is associated with high cost of management and significant morbidity. Yet, there is a lack of population-based epidemiologic studies using current definitions of CRSwNP, and the mechanisms that drive pathogenesis in this disease remain unclear. In this review, we summarize the current evidence for the plethora of factors that likely contribute to CRSwNP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, group 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRSwNP. In addition to the development of new tools and models to aid mechanistic studies, the field of CRSwNP research also needs the type of robust epidemiologic data that has served the asthma community so well. Given the high prevalence, costs and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients who suffer from this disease. PMID:25482020

  2. General amyloid inhibitors? A critical examination of the inhibition of IAPP amyloid formation by inositol stereoisomers.

    Directory of Open Access Journals (Sweden)

    Hui Wang

    Full Text Available Islet amyloid polypeptide (IAPP or amylin forms amyloid deposits in the islets of Langerhans; a process that is believed to contribute to the progression of type 2 diabetes and to the failure of islet transplants. An emerging theme in amyloid research is the hypothesis that the toxic species produced during amyloid formation by different polypeptides share common features and exert their effects by common mechanisms. If correct, this suggests that inhibitors of amyloid formation by one polypeptide might be effective against other amyloidogenic sequences. IAPP and Aβ, the peptide responsible for amyloid formation in Alzheimer's disease, are particularly interesting in this regard as they are both natively unfolded in their monomeric states and share some common characteristics. Comparatively little effort has been expended on the design of IAPP amyloid inhibitors, thus it is natural to inquire if Aβ inhibitors are effective against IAPP, especially since no IAPP inhibitors have been clinically approved. A range of compounds inhibit Aβ amyloid formation, including various stereoisomers of inositol. Myo-, scyllo-, and epi-inositol have been shown to induce conformational changes in Aβ and prevent Aβ amyloid fibril formation by stabilizing non-fibrillar β-sheet structures. We investigate the ability of inositol stereoisomers to inhibit amyloid formation by IAPP. The compounds do not induce a conformational change in IAPP and are ineffective inhibitors of IAPP amyloid formation, although some do lead to modest apparent changes in IAPP amyloid fibril morphology. Thus not all classes of Aβ inhibitors are effective against IAPP. This work provides a basis of comparison to work on polyphenol based inhibitors of IAPP amyloid formation and helps provide clues as to the features which render them effective. The study also helps provide information for further efforts in rational inhibitor design.

  3. Restraint stress and repeated CRF receptor activation in the amygdala both increase amyloid β precursor protein (APP) and amyloid-β (Aβ) peptide but have divergent effects on BDNF and pre-synaptic proteins in the prefrontal cortex of rats

    OpenAIRE

    Ray, Balmiki; Gaskins, Denise L.; Sajdyk, Tammy J.; Spence, John P.; Fitz, Stephanie D.; Shekhar, Anantha; Lahiri, Debomoy K.

    2011-01-01

    Both environmental stress and anxiety may represent important risk factors for Alzheimer's disease (AD) pathogenesis. Previous studies demonstrate that restraint stress is associated with increased amyloid beta (Aβ) and decreased brain-derived neurotrophic factor (BDNF) levels in the brain. Aβ deposition, synaptic loss, and neurodegeneration define major hallmarks of AD, and BDNF is responsible for the maintenance of neurons. In contrast to restraint stress, repeated injections of sub-anxioge...

  4. Binding of ACE-inhibitors to in vitro and patient-derived amyloid-β fibril models

    Science.gov (United States)

    Bhavaraju, Manikanthan; Phillips, Malachi; Bowman, Deborah; Aceves-Hernandez, Juan M.; Hansmann, Ulrich H. E.

    2016-01-01

    Currently, no drugs exist that can prevent or reverse Alzheimer's disease, a neurodegenerative disease associated with the presence, in the brain, of plaques that are composed of β-amyloid (Aβ) peptides. Recent studies suggest that angiotensin-converting enzyme (ACE) inhibitors, a set of drugs used to treat hypertension, may inhibit amyloid formation in vitro. In the present study, we investigate through computer simulations the binding of ACE inhibitors to patient-derived Aβ fibrils and contrast it with that of ACE inhibitors binding to in vitro generated fibrils. The binding affinities of the ACE inhibitors are compared with that of Congo red, a dye that is used to identify amyloid structures and that is known to be a weak inhibitor of Aβ aggregation. We find that ACE inhibitors have a lower binding affinity to the patient-derived fibrils than to in vitro generated ones. For patient-derived fibrils, their binding affinities are even lower than that of Congo red. Our observations raise doubts on the hypothesis that these drugs inhibit fibril formation in Alzheimer patients by interacting directly with the amyloids.

  5. Image Analysis for Contrast Enhanced Ultrasound Carotid Plaque Imaging

    NARCIS (Netherlands)

    Z. Akkus (Zeynettin)

    2014-01-01

    markdownabstract__Abstract__ Intraplaque neovascularization (IPN) has been presented as an important biomarker for progressive atherosclerotic disease and plaque vulnerability in several pathological studies. Therefore, quantification of IPN may allow early prediction of plaque at risk of rupture a

  6. High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease

    Science.gov (United States)

    Plascencia-Villa, Germán; Ponce, Arturo; Collingwood, Joanna F.; Arellano-Jiménez, M. Josefina; Zhu, Xiongwei; Rogers, Jack T.; Betancourt, Israel; José-Yacamán, Miguel; Perry, George

    2016-04-01

    Abnormal accumulation of brain metals is a key feature of Alzheimer’s disease (AD). Formation of amyloidplaque cores (APC) is related to interactions with biometals, especially Fe, Cu and Zn, but their particular structural associations and roles remain unclear. Using an integrative set of advanced transmission electron microscopy (TEM) techniques, including spherical aberration-corrected scanning transmission electron microscopy (Cs-STEM), nano-beam electron diffraction, electron holography and analytical spectroscopy techniques (EDX and EELS), we demonstrate that Fe in APC is present as iron oxide (Fe3O4) magnetite nanoparticles. Here we show that Fe was accumulated primarily as nanostructured particles within APC, whereas Cu and Zn were distributed through the amyloid fibers. Remarkably, these highly organized crystalline magnetite nanostructures directly bound into fibrillar Aβ showed characteristic superparamagnetic responses with saturated magnetization with circular contours, as observed for the first time by off-axis electron holography of nanometer scale particles.

  7. Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both β-amyloid production and clearance.

    Science.gov (United States)

    Zhu, Zhiyuan; Yan, Jianming; Jiang, Wei; Yao, Xin-gang; Chen, Jing; Chen, Lili; Li, Chenjing; Hu, Lihong; Jiang, Hualiang; Shen, Xu

    2013-08-01

    Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery. PMID:23926267

  8. Increased tauopathy drives microglia-mediated clearance of beta-amyloid.

    Science.gov (United States)

    Chen, Wesley; Abud, Edsel A; Yeung, Stephen T; Lakatos, Anita; Nassi, Trevor; Wang, Jane; Blum, David; Buée, Luc; Poon, Wayne W; Blurton-Jones, Mathew

    2016-01-01

    Alzheimer disease is characterized by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aβ deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aβ accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aβ plaque load and insoluble Aβ species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aβ and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aβ and that tau-induced changes in microglial activation state can promote the clearance of Aβ. PMID:27339073

  9. Synthesis and biological evaluation of indole-chalcone derivatives as β-amyloid imaging probe.

    Science.gov (United States)

    Cui, Mengchao; Ono, Masahiro; Kimura, Hiroyuki; Liu, Bo Li; Saji, Hideo

    2011-02-01

    A series of chaclone derivatives containing an indole moiety were evaluated in competitive binding assays with Aβ(1-42) aggregates versus [(125)I]IMPY. The affinity of these compounds ranged from 4.46 to >1008 nM, depending on the substitution on the phenyl ring. Fluorescent staining in vitro showed that one compound with a N,N-dimethylamino group intensely stained Aβ plaques within brain sections of AD transgenic mice. The radioiodinated probe [(125)I]-(E)-3-(1H-indol-5-yl)-1-(4-iodophenyl)prop-2-en-1-one, [(125)I]4, was prepared and autoradiography in sections of brain tissue from an animal model of AD showed that it labeled Aβ plaques specifically. However, experiments with normal mice indicated that [(125)I]4 exhibited a low uptake into the brain in vivo (0.41% ID/g at 2 min). Additional chemical modifications of this indole-chalcone structure may lead to more useful imaging agents for detecting β-amyloid plaques in the brains of AD patients. PMID:21216142

  10. In vivo amyloid-β imaging in the APPPS1-21 transgenic mouse model with a 89Zr- labeled monoclonal antibody.

    Directory of Open Access Journals (Sweden)

    Ann-Marie eWaldron

    2016-03-01

    Full Text Available Introduction: The accumulation of amyloid-β is a pathological hallmark of Alzheimer’s disease and is a target for molecular imaging probes to aid in diagnosis and disease monitoring. This study evaluated the feasibility of using a radiolabeled monoclonal anti-amyloid-β antibody (JRF/AβN/25 to non-invasively assess amyloid-β burden in aged transgenic mice (APPPS1-21 with μPET imaging.Methods: We investigated the antibody JRF/AβN/25 that binds to full-length Aβ. JRF/AβN/25 was radiolabeled with a [89Zr]-desferal chelate and intravenously injected into 12-13 month aged APPPS1-21 mice and their wild-type (WT controls. Mice underwent in vivo μPET imaging at 2, 4 and 7 days post injection and were sacrificed at the end of each time point to assess brain penetrance, plaque labeling, biodistribution and tracer stability. To confirm imaging specificity we also evaluated brain uptake of a non-amyloid targeting [89Zr]-labeled antibody (Trastuzumab as a negative control, additionally we performed a competitive blocking study with non-radiolabeled Df-Bz-JRF/AβN/25 and finally we assessed the possible confounding effects of blood retention. Results: Voxel-wise analysis of μPET data demonstrated significant [89Zr]-Df-Bz-JRF/AβN/25 retention in APPPS1-21 mice at all time points investigated. With ex vivo measures of radioactivity, significantly higher retention of [89Zr]-Df-Bz-JRF/AβN/25 was found at 4 and 7 day pi in APPPS1-21 mice. Despite the observed genotypic differences, comparisons with immunohistochemistry revealed that in vivo plaque labeling was low. Furthermore, pre-treatment with Df-Bz-JRF/AβN/25 only partially blocked [89Zr]-Df-Bz-JRF/AβN/25 uptake indicative of a high contribution of non-specific binding. Conclusion: Amyloid plaques were detected in vivo with a radiolabeled monoclonal anti-amyloid antibody. The low brain penetrance of the antibodies in addition to non-specific binding prevented an accurate estimation of plaque

  11. Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer’s Disease

    Science.gov (United States)

    Sung, Hye Youn; Choi, Byung-Ok; Jeong, Jee Hyang; Kong, Kyoung Ae; Hwang, Jinha; Ahn, Jung-Hyuck

    2016-01-01

    To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer’s disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located −374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2′-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at −374 promoter CpG site was correlated with increased HMOX1expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at −374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the −374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and

  12. Plaque rupture in humans and mice

    DEFF Research Database (Denmark)

    Schwartz, Stephen M; Galis, Zorina S; Rosenfeld, Michael E;

    2007-01-01

    Despite the many studies of murine atherosclerosis, we do not yet know the relevance of the natural history of this model to the final events precipitated by plaque disruption of human atherosclerotic lesions. The literature has become particularly confused because of the common use of terms such...

  13. The high-risk plaque initiative

    DEFF Research Database (Denmark)

    Falk, Erling; Sillesen, Henrik; Muntendam, Pieter;

    2011-01-01

    The High-Risk Plaque (HRP) Initiative is a research and development effort to advance the understanding, recognition, and management of asymptomatic individuals at risk for a near-term atherothrombotic event such as myocardial infarction or stroke. Clinical studies using the newest technologies...... discovery studies. All individuals will be followed until 600 major atherothrombotic events have occurred in those undergoing imaging....

  14. Inflamed psoriatic plaques: Drug toxicity or disease exacerbation?

    Directory of Open Access Journals (Sweden)

    Nidhi Jindal

    2013-01-01

    Full Text Available We are presenting a case of Methotrexate treated stable plaque psoriasis, in whom inflamed psoriatic plaques of drug toxicity were misdiagnosed as disease exacerbation. Erosive psoriatic plaques were present in the absence of biochemical or hematological derangements. Ulceration of psoriatic plaques in the presence of disturbed hematological profile is well described as a harbinger of methotrexate toxicity, but this kind of erosions in the absence of any systemic involvement is the first report of its kind.

  15. A radiochemical assay for glycolytic activity in dental plaque

    International Nuclear Information System (INIS)

    A radiochemical technique for the rapid and precise measurement of glucose utilization of fresh samples of dental plaque is described. The method appears to be a sensitive indicator of the actual glycolytic ability of an organized microbial plaque including activity in the Embden-Meyerhof pathway as well as heterolactic fermentation and the Entner-Doudoroff pathway. It was found that the glycolytic rate of plaque associated with periodontal pockets was significantly higher than that for plaque not so associated. (author)

  16. Characterization of bacteriophage communities and CRISPR profiles from dental plaque

    OpenAIRE

    Naidu, Mayuri; Robles-Sikisaka, Refugio; Abeles, Shira R.; Boehm, Tobias K; Pride, David T

    2014-01-01

    Background Dental plaque is home to a diverse and complex community of bacteria, but has generally been believed to be inhabited by relatively few viruses. We sampled the saliva and dental plaque from 4 healthy human subjects to determine whether plaque was populated by viral communities, and whether there were differences in viral communities specific to subject or sample type. Results We found that the plaque was inhabited by a community of bacteriophage whose membership was mostly subject-...

  17. Reliability and discriminatory power of methods for dental plaque quantification

    OpenAIRE

    Daniela Prócida Raggio; Mariana Minatel Braga; Jonas Almeida Rodrigues; Patrícia Moreira de Freitas; José Carlos Pettorossi Imparato; Fausto Medeiros Mendes

    2010-01-01

    OBJECTIVE: This in situ study evaluated the discriminatory power and reliability of methods of dental plaque quantification and the relationship between visual indices (VI) and fluorescence camera (FC) to detect plaque. MATERIAL AND METHODS: Six volunteers used palatal appliances with six bovine enamel blocks presenting different stages of plaque accumulation. The presence of plaque with and without disclosing was assessed using VI. Images were obtained with FC and digital camera in both cond...

  18. Fibrillar amyloid-β-activated human astroglia kill primary human neurons via neutral sphingomyelinase: Implications for Alzheimer’s disease

    OpenAIRE

    Jana, Arundhati; Pahan, Kalipada

    2010-01-01

    Glial activation plays an important role in the pathogenesis of various neurodegenerative disorders including Alzheimer’s disease (AD). However, molecular mechanisms by which activated glia could kill neurons are poorly understood. The present study underlines the importance of neutral sphingomyelinase (N-SMase) in mediating the damaging effect of fibrillar amyloid-β 1-42 (Aβ1-42) peptide-activated astroglia on neurons. In trans-well experiments, soluble products released from activated prima...

  19. Pathogenesis of Candida vulvovaginitis.

    Science.gov (United States)

    Sobel, J D

    1989-01-01

    The occurrence of candida vulvovaginitis (CVV) has been estimated based on statistical data from Great Britain to be an increase to 200/100,000 over 10 years to 1984. CVV in the US is the 2nd commonest cause of vaginal infection, with bacterial vaginosis occurring twice as often. 85-90% of the yeasts isolated from the vagina are candida albicans, based on biotyping rather that the newer methods of DNA hybridization. The pathogenesis of CVV is discussed in terms of the microbiology (virulence factors, adherence, germ tube and mycelium formation, proteinase secretion, and switching colonies), asymptomatic vaginal colonization, transformation to symptomatic vaginitis, host predisposing factors (pregnancy, oral contraceptives, diabetes mellitus, antimicrobes, and other), vaginal defense mechanisms (humoral system, phagocytic system, cell mediated immunity, vaginal flora, other), and pathogenesis of recurrent and chronic CVV (internal reservoir, sexual transmission, vaginal relapse, and experimental models) The discussion of the development of virulent symptoms is capsuled in the following comments. Vaginal cell receptivity varies among individuals, but all strains of C. Albicans adhere to both exfoliated vaginal and buccal epithelial cells, or mucosal surfaces, through the yeast surface mannoprotein. It is suggested from in vitro studies that germ tube and mycelium formation facilitates vaginal mucosal invasion. Exogenous and endogenous factors may enhance germination and precipitate symptomatic vaginitis, or inhibit germination. Increased proteinase secretion may be a result of the transformation from the blastoconidium/colonization phase to the germinated invasive vaginitis stage or an independent virulence factor. It is reported that hereditable spontaneous switching may occur spontaneously in vivo also. Colonizing yeasts with a change in environment can transform to a more virulent phase. Colonization rates vary from 10-25%, and the critical issue is understanding

  20. Aterofisiol® in carotid plaque evolution

    Directory of Open Access Journals (Sweden)

    Amato B

    2015-07-01

    Full Text Available Bruno Amato,1,2,* Rita Compagna,1,2,* Maurizio Amato,2 Luca Gallelli,3 Stefano de Franciscis,1,4,* Raffaele Serra1–4,*1Interuniversity Center of Phlebolymphology (CIFL, International Research and Educational Program in Clinical and Experimental Biotechnology, University Magna Graecia of Catanzaro, Catanzaro, 2Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, 3Department of Health Sciences, University of Catanzaro, Catanzaro, 4Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy*These authors contributed equally to this workBackground: In patients with carotid stenosis, the risk of plaque rupture is related to the composition of the atherosclerotic plaque rather than to its magnitude. In this regard, we evaluated the effects of a supplement, Aterofisiol,® containing omega-3 (EPA [eicosapen acid] DHA [docosahexaenoic acid], vitamin K2, vitamin B6, vitamin B12, oligomeric proanthocyanidins (OPC and resveratrol on the composition of atherosclerotic plaque and on neurological symptoms in patients with carotid stenosis undergoing carotid endarterectomy.Methods: The study was randomized, prospective, and double-blinded. Eligible patients were of both sexes, with carotid stenosis >70% who underwent endarterectomy. Enrolled patients were randomly allocated to receive either one tablet of acetylsalicylic acid 100 mg (Cardioaspirin® + one tablet of Aterofisiol every 24 hours or one tablet of Cardioaspirin + one tablet of placebo every 24 hours. Each treatment was started 30 days before the surgery and was stopped 5 days before the surgery. The plaques were removed “en bloc” using standard surgical technique.Results: During the study period, 214 patients (135 men and 79 women were enrolled for intent-to-treat and randomized in two groups: Group A: 107 patients (68 men and 39 women were treated with Cardioaspirin + Aterofisiol. Group B: 107 patients (67 men and 40

  1. In vivo and in vitro evidence that 99mTc-HYNIC-interleukin-2 is able to detect T lymphocytes in vulnerable atherosclerotic plaques of the carotid artery

    International Nuclear Information System (INIS)

    Recent advances in basic science have established that inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Inflammatory cells are thought to be responsible for the transformation of a stable plaque into a vulnerable one. Lymphocytes constitute at least 20 % of infiltrating cells in these vulnerable plaques. Therefore, the interleukin-2 (IL-2) receptor, being overexpressed on activated T lymphocytes, may represent an attractive biomarker for plaque vulnerability. The aim of this study was to evaluate the specificity of radiolabelled IL-2 [99mTc-hydrazinonicotinamide (HYNIC)-IL-2] for imaging the lymphocytic infiltration in carotid plaques in vivo by planar and single photon emission computed tomography (SPECT)/CT imaging and ex vivo by microSPECT and autoradiography. For the in vivo study, ten symptomatic patients with advanced plaques at ultrasound who were scheduled for carotid endarterectomy underwent 99mTc-HYNIC-IL-2 scintigraphy. The images were analysed visually on planar and SPECT images and semi-quantitatively on SPECT images by calculating target to background (T/B) ratios. After endarterectomy, immunomorphological evaluation and immunophenotyping were performed on plaque slices. For the ex vivo studies, four additional patients were included and, after in vitro incubation of removed plaques with 99mTc-HYNIC-IL-2, autoradiography was performed and microSPECT images were acquired. Visual analysis defined clear 99mTc-HYNIC-IL-2 uptake in seven of the ten symptomatic plaques. SPECT/CT allowed visualization in eight of ten. A significant correlation was found between the number of CD25+ lymphocytes and the total number of CD25+ cells in the plaque and the T/B ratio with adjacent carotid artery as background (Pearson's r = 0.89, p = 0.003 and r = 0.87, p = 0.005, respectively). MicroSPECT imaging showed clear 99mTc-HYNIC-IL-2 uptake within the plaque wall and not in the lipidic core. With autoradiography, only CD3+ lymphocytes were found to

  2. Three-dimensional carotid ultrasound plaque texture predicts vascular events

    DEFF Research Database (Denmark)

    van Engelen, Arna; Wannarong, Thapat; Parraga, Grace;

    2014-01-01

    BACKGROUND AND PURPOSE: Carotid ultrasound atherosclerosis measurements, including those of the arterial wall and plaque, provide a way to monitor patients at risk of vascular events. Our objective was to examine carotid ultrasound plaque texture measurements and the change in carotid plaque...

  3. Tensile and compressive properties of fresh human carotid atherosclerotic plaques.

    LENUS (Irish Health Repository)

    Maher, Eoghan

    2009-12-11

    Accurate characterisation of the mechanical properties of human atherosclerotic plaque is important for our understanding of the role of vascular mechanics in the development and treatment of atherosclerosis. The majority of previous studies investigating the mechanical properties of human plaque are based on tests of plaque tissue removed following autopsy. This study aims to characterise the mechanical behaviour of fresh human carotid plaques removed during endarterectomy and tested within 2h. A total of 50 radial compressive and 17 circumferential tensile uniaxial tests were performed on samples taken from 14 carotid plaques. The clinical classification of each plaque, as determined by duplex ultrasound is also reported. Plaques were classified as calcified, mixed or echolucent. Experimental data indicated that plaques were highly inhomogeneous; with variations seen in the mechanical properties of plaque obtained from individual donors and between donors. The mean behaviour of samples for each classification indicated that calcified plaques had the stiffest response, while echolucent plaques were the least stiff. Results also indicated that there may be a difference in behaviour of samples taken from different anatomical locations (common, internal and external carotid), however the large variability indicates that more testing is needed to reach significant conclusions. This work represents a step towards a better understanding of the in vivo mechanical behaviour of human atherosclerotic plaque.

  4. MRI-based Biomechanical Modeling of Carotid Atherosclerotic Plaques: The stable plaque paradigm

    OpenAIRE

    Nieuwstadt, Harm

    2015-01-01

    markdownabstract__Abstract__ Carotid atherosclerosis is a common cause of acute ischemic stroke and places a major burden on worldwide health-related quality of life. The currently-used stenosis-degree guidelines to decide on surgical intervention through carotid endarterectomy in order to prevent a future event are imperfect. This is because they insufficiently target plaque vulnerability. To provide an alternative carotid plaque vulnerability assessment, one can compute the biomechanical pe...

  5. Characterization of cDNA encoding a human sperm membrane protein related to A4 amyloid protein.

    OpenAIRE

    Yan, Y C; Bai, Y.(Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China); Wang, L.F.; Miao, S Y; Koide, S S

    1990-01-01

    A rat testis lambda gt11 cDNA library was screened with a monoclonal antibody raised against a human sperm membrane protein designated YWK-II. A clone was found with a cDNA insert composed of 1837 base pairs that contained an open reading frame coding for 191 amino acid residues. The deduced polypeptide contained a segment with high homology to the transmembrane-cytoplasmic domains of the A4 amyloid protein found in brain plaques of Alzheimer disease patients. A sequence of basic amino acid r...

  6. Recent progress in melasma pathogenesis.

    Science.gov (United States)

    Lee, Ai-Young

    2015-11-01

    Melasma is a common skin pigmentation condition. Given therapeutic difficulty as one of the biggest concerns, understanding of the etiology and pathogenesis of melasma becomes essential. UV irradiation, female sex hormones, and inflammatory processes are addressed as triggering factors with genetic predisposition. The mechanism of UV-induced melanogenesis has been extensively investigated as a model system to study melasma pathogenesis. Hitherto, treatment modalities for melasma are similar to other hyperpigmentation disorders. However, individual triggering factors induce a separate pigmentation disease, whose pathogenic mechanisms and clinical phenotypes are different from the ones encountered in melasma. Fortunately, there have been ongoing updates on melasma pathogenesis with regard to major triggering factors. Presence of certain factors working independently of UV exposure and role of dermal factors and microRNAs are being identified as novel discoveries about melasma pathogenesis. In this review, the melasma pathogenesis is reviewed in association with updated and new findings. PMID:26230865

  7. Midlife adiposity predicts earlier onset of Alzheimer's dementia, neuropathology and presymptomatic cerebral amyloid accumulation.

    Science.gov (United States)

    Chuang, Y-F; An, Y; Bilgel, M; Wong, D F; Troncoso, J C; O'Brien, R J; Breitner, J C; Ferruci, L; Resnick, S M; Thambisetty, M

    2016-07-01

    Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer's disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer's neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer's neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer's neuropathology. A healthy BMI at midlife may delay the onset of AD. PMID:26324099

  8. Amyloid-beta: a crucial factor in Alzheimer's disease.

    Science.gov (United States)

    Sadigh-Eteghad, Saeed; Sabermarouf, Babak; Majdi, Alireza; Talebi, Mahnaz; Farhoudi, Mehdi; Mahmoudi, Javad

    2015-01-01

    Alzheimer's disease (AD) is the most prevalent form of dementia which affects people older than 60 years of age. In AD, the dysregulation of the amyloid-beta (Aβ) level leads to the appearance of senile plaques which contain Aβ depositions. Aβ is a complex biological molecule which interacts with many types of receptors and/or forms insoluble assemblies and, eventually, its nonphysiological depositions alternate with the normal neuronal conditions. In this situation, AD signs appear and the patients experience marked cognitional disabilities. In general, intellect, social skills, personality, and memory are influenced by this disease and, in the long run, it leads to a reduction in quality of life and life expectancy. Due to the pivotal role of Aβ in the pathobiology of AD, a great deal of effort has been made to reveal its exact role in neuronal dysfunctions and to finding efficacious therapeutic strategies against its adverse neuronal outcomes. Hence, the determination of its different molecular assemblies and the mechanisms underlying its pathological effects are of interest. In the present paper, some of the well-established structural forms of Aβ, its interactions with various receptors and possible molecular and cellular mechanisms underlying its neurotoxicity are discussed. In addition, several Aβ-based rodent models of AD are reviewed. PMID:25471398

  9. Amyloid oligomer structure characterization from simulations: A general method

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Phuong H., E-mail: phuong.nguyen@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Li, Mai Suan [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland); Derreumaux, Philippe, E-mail: philippe.derreumaux@ibpc.fr [Laboratoire de Biochimie Théorique, UPR 9080, CNRS Université Denis Diderot, Sorbonne Paris Cité IBPC, 13 rue Pierre et Marie Curie, 75005 Paris (France); Institut Universitaire de France, 103 Bvd Saint-Germain, 75005 Paris (France)

    2014-03-07

    Amyloid oligomers and plaques are composed of multiple chemically identical proteins. Therefore, one of the first fundamental problems in the characterization of structures from simulations is the treatment of the degeneracy, i.e., the permutation of the molecules. Second, the intramolecular and intermolecular degrees of freedom of the various molecules must be taken into account. Currently, the well-known dihedral principal component analysis method only considers the intramolecular degrees of freedom, and other methods employing collective variables can only describe intermolecular degrees of freedom at the global level. With this in mind, we propose a general method that identifies all the structures accurately. The basis idea is that the intramolecular and intermolecular states are described in terms of combinations of single-molecule and double-molecule states, respectively, and the overall structures of oligomers are the product basis of the intramolecular and intermolecular states. This way, the degeneracy is automatically avoided. The method is illustrated on the conformational ensemble of the tetramer of the Alzheimer's peptide Aβ{sub 9−40}, resulting from two atomistic molecular dynamics simulations in explicit solvent, each of 200 ns, starting from two distinct structures.

  10. DBA/2J genetic background exacerbates spontaneous lethal seizures but lessens amyloid deposition in a mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Harriet M Jackson

    Full Text Available Alzheimer's disease (AD is a leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles (NFTs and neuronal dysfunction. Early onset AD (EOAD is commonly caused by mutations in amyloid precursor protein (APP or genes involved in the processing of APP including the presenilins (e.g. PSEN1 or PSEN2. In general, mouse models relevant to EOAD recapitulate amyloidosis, show only limited amounts of NFTs and neuronal cell dysfunction and low but significant levels of seizure susceptibility. To investigate the effect of genetic background on these phenotypes, we generated APPswe and PSEN1de9 transgenic mice on the seizure prone inbred strain background, DBA/2J. Previous studies show that the DBA/2J genetic background modifies plaque deposition in the presence of mutant APP but the impact of PSEN1de9 has not been tested. Our study shows that DBA/2J.APPswePSEN1de9 mice are significantly more prone to premature lethality, likely to due to lethal seizures, compared to B6.APPswePSEN1de9 mice-70% of DBA/2J.APPswePSEN1de9 mice die between 2-3 months of age. Of the DBA/2J.APPswePSEN1de9 mice that survived to 6 months of age, plaque deposition was greatly reduced compared to age-matched B6.APPswePSEN1de9 mice. The reduction in plaque deposition appears to be independent of microglia numbers, reactive astrocytosis and complement C5 activity.

  11. Amyloid Imaging in Aging and Dementia: Testing the Amyloid Hypothesis In Vivo

    Directory of Open Access Journals (Sweden)

    G. D. Rabinovici

    2009-01-01

    Full Text Available Amyloid imaging represents a major advance in neuroscience, enabling the detection and quantification of pathologic protein aggregations in the brain. In this review we survey current amyloid imaging techniques, focusing on positron emission tomography (PET with ^{11}carbon-labelled Pittsburgh Compound-B (11C-PIB, the most extensively studied and best validated tracer. PIB binds specifically to fibrillar beta-amyloid (Aβ deposits, and is a sensitive marker for Aβ pathology in cognitively normal older individuals and patients with mild cognitive impairment (MCI and Alzheimer’s disease (AD. PIB-PET provides us with a powerful tool to examine in vivo the relationship between amyloid deposition, clinical symptoms, and structural and functional brain changes in the continuum between normal aging and AD. Amyloid imaging studies support a model in which amyloid deposition is an early event on the path to dementia, beginning insidiously in cognitively normal individuals, and accompanied by subtle cognitive decline and functional and structural brain changes suggestive of incipient AD. As patients progress to dementia, clinical decline and neurodegeneration accelerate and proceed independently of amyloid accumulation. In the future, amyloid imaging is likely to supplement clinical evaluation in selecting patients for anti-amyloid therapies, while MRI and FDG-PET may be more appropriate markers of clinical progression.

  12. Sumoylation and Human Disease Pathogenesis

    OpenAIRE

    Sarge, Kevin D.; Park-Sarge, Ok-Kyong

    2009-01-01

    Covalent modification by SUMO polypeptides, or sumoylation, is an important regulator of the functional properties of many proteins. Among these are a number of proteins implicated in human diseases, including cancer, Huntington’s, Alzheimer’s, and Parkinson’s Diseases, as well as spinocerebellar ataxia 1 and amyotrophic lateral sclerosis. Recent reports reveal two new examples of human disease-associated proteins that are SUMO modified: amyloid precursor protein and lamin A. These findings p...

  13. Pathogenesis of and therapeutic strategies to ameliorate the transthyretin amyloidoses.

    Science.gov (United States)

    Sekijima, Yoshiki; Kelly, Jeffery W; Ikeda, Shu-ichi

    2008-01-01

    Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials. PMID:19075702

  14. The pathogenesis of amyloidosis in periodic disease: Some aspects

    Directory of Open Access Journals (Sweden)

    Z. T. Djndoyan

    2014-07-01

    Full Text Available Sufficient information indicating the implication of dysfunction of interleukins (IL-6 and IL-1 in particular in the pathogenesis of amyloidosis in a number of autoinflammatory, rheumatic, and autoimmune diseases, including those in periodic disease (PD, has been recently accumulated. Its genetic defect – pirin mutation – gives rise to an alternative innate immune response (phagocytic cell activation to secrete IL-1 by macrophages and to activate T-helper cells. This causes imbalance in the synthesis of proinflammatory (IL-6, IL-8, and TNF-α and anti-inflammatory (IL-4, IL-10, and IL-1 receptor antagonist cytokines. Moreover, the uncontrolled macrophage (monocyte secretion of a great deal of IL-6 that together with IL-1 is a mediator of the synthesis of the serum amyloid fibril protein precursor SAA by hepatocytes, neutrophils, and fibroblasts plays one of the key roles in the pathogenesis of PD through amyloidosis. With this, IL-6 stimulates the inflammatory process, by enhancing the release of lysosomal enzymes, reactive oxygen species, and eicosanoids (prostaglandins, leukotrienes, thromboxane from the polymorphic nuclear leukocytes, macrophages, endotheliocytes, and fibroblasts and by augmenting the chemotaxis of macrophages and neutrophils, and the degranulation of the latter, i.e. through its action on the effector cells of inflammation, and prepares the tissue basis for amyloid deposits in this fashion. Thus, the analysis of literary and own materials gives grounds to suggest that pirin mutation is a trigger of the synthesis of IL-1 and IL-6 in PD and their hypersecretion is an initial link of the synthesis of SAA.

  15. Correlation of plaque nitric oxide levels with plaque Streptococcus mutans, plaque pH and decayed, missing and filled teeth index of children of different age groups

    OpenAIRE

    Sawinderjit Saini; Hina Noorani; P K Shivaprakash

    2016-01-01

    Context: Dental plaque is considered one of the most important etiological factors for dental caries. Nitrate and Nitrite levels in saliva are considered protective against oral and gastrointestinal disease. Plaque nitric oxide (NO) levels and its role in dental caries has not be explored in the literature. Aim: Determine the correlation of the plaque nitric oxide (NO) with dental caries in vivo. Materials and Method: 75 healthy children between ages of 3-15 years were selected. The age, stat...

  16. Assessment of carotid plaque vulnerability using structural and geometrical determinants

    International Nuclear Information System (INIS)

    Because many acute cerebral ischemic events are caused by rupture of vulnerable carotid atheroma and subsequent thrombosis, the present study used both idealized and patient-specific carotid atheromatous plaque models to evaluate the effect of structural determinants on stress distributions within plaque. Using a finite element method, structural analysis was performed using models derived from in vivo high-resolution magnetic resonance imaging (MRI) of carotid atheroma in 40 non-consecutive patients (20 symptomatic, 20 asymptomatic). Plaque components were modeled as hyper-elastic materials. The effects of varying fibrous cap thickness, lipid core size and lumen curvature on plaque stress distributions were examined. Lumen curvature and fibrous cap thickness were found to be major determinants of plaque stress. The size of the lipid core did not alter plaque stress significantly when the fibrous cap was relatively thick. The correlation between plaque stress and lumen curvature was significant for both symptomatic (p=0.01; correlation coefficient: 0.689) and asymptomatic patients (p=0.01; correlation coefficient: 0.862). Lumen curvature in plaques of symptomatic patients was significantly larger than those of asymptomatic patients (1.50±1.0 mm-1 vs 1.25±0.75 mm-1; p=0.01). Specific plaque morphology (large lumen curvature and thin fibrous cap) is closely related to plaque vulnerability. Structural analysis using high-resolution MRI of carotid atheroma may help in detecting vulnerable atheromatous plaque and aid the risk stratification of patients with carotid disease. (author)

  17. 18FDG PET and ultrasound echolucency in carotid artery plaques

    DEFF Research Database (Denmark)

    Graebe, Martin; Pedersen, Sune F; Højgaard, Liselotte;

    2010-01-01

    ultrasound and PET imaging. Plaque standardized gray scale medians (GSM) were measured in longitudinal ultrasound images to quantitate echolucency, and GSM values were compared with FDG PET uptake quantified by maximum standardized uptake values (SUV). Symptomatic plaques were compared with contralateral...... carotid artery plaques considered asymptomatic, and in 17 symptomatic patients, endarterectomized plaque specimens were analyzed for CD68 expression. RESULTS: There was a negative correlation between GSM and FDG SUV (r = -0.56, p < 0.01). Whereas echo-rich plaques tended to show low FDG uptake, echolucent...... plaques ranged from high to low inflammatory activity, as depicted with PET. Quantitative FDG SUV differentiated asymptomatic from symptomatic plaques, whereas GSM values did not. There was a positive correlation between CD68 expression and FDG uptake (r = 0.50, p = 0.04). CONCLUSIONS: Our results...

  18. Reliability and discriminatory power of methods for dental plaque quantification

    Directory of Open Access Journals (Sweden)

    Daniela Prócida Raggio

    2010-04-01

    Full Text Available OBJECTIVE: This in situ study evaluated the discriminatory power and reliability of methods of dental plaque quantification and the relationship between visual indices (VI and fluorescence camera (FC to detect plaque. MATERIAL AND METHODS: Six volunteers used palatal appliances with six bovine enamel blocks presenting different stages of plaque accumulation. The presence of plaque with and without disclosing was assessed using VI. Images were obtained with FC and digital camera in both conditions. The area covered by plaque was assessed. Examinations were done by two independent examiners. Data were analyzed by Kruskal-Wallis and Kappa tests to compare different conditions of samples and to assess the inter-examiner reproducibility. RESULTS: Some methods presented adequate reproducibility. The Turesky index and the assessment of area covered by disclosed plaque in the FC images presented the highest discriminatory powers. CONCLUSION: The Turesky index and images with FC with disclosing present good reliability and discriminatory power in quantifying dental plaque.

  19. Genetics Home Reference: hereditary cerebral amyloid angiopathy

    Science.gov (United States)

    ... prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of hereditary cerebral amyloid angiopathy is unknown. The Dutch type is the most common, with over 200 ...

  20. Molecular mechanisms of amyloid self-regulation

    OpenAIRE

    Landreh, Michael

    2012-01-01

    Amyloid is associated with both pathological protein deposits and the formation of functional protein structures. Therefore, several strategies have evolved to control the formation or inhibition of amyloid in vivo. In this thesis, three separate systems were investigated in which amyloidogenic protein segments are coupled to regulatory elements that prevent or promote fibrillation. We describe the molecular mechanism for how (a) a propeptide segment prevents the uncontrolled a...

  1. Amyloid myopathy presenting with respiratory failure.

    OpenAIRE

    Ashe, J.; Borel, C O; Hart, G.; Humphrey, R L; Derrick, D A; Kuncl, R W

    1992-01-01

    Amyloidosis is a rare cause of myopathy. Its prominent or presenting feature may be respiratory failure. Physiological measurement of transdiaphragmatic pressure and biopsy specimens of muscle show the pathological mechanism to be diaphragm weakness due to amyloid infiltration of the diaphragm rather than parenchymal lung involvement. Thus amyloid myopathy even without the typical macroglossia and muscle pseudohypertrophy should be considered as one of the neurological causes of respiratory f...

  2. Oculocutaneous albinism complicated with an ulcerated plaque

    Directory of Open Access Journals (Sweden)

    Lokanatha Keshavalu

    2013-04-01

    Full Text Available A 32-year-old male with a history of albinism and farmer by occupation presented with an ulcerated plaque on the right wrist. The patient had light eyes, hair, and skin. Physical examination showed extensive photodamage. A skin biopsy specimen from the plaque revealed a well-differentiated squamous-cell carcinoma. Wide surgical excision was done. The most common types of oculocutaneous albinism (OCA, OCA 1 and OCA 2, are autosomal recessive disorders of pigmentation that commonly affect the skin, hair and eyes. Photodamage and skin cancers plague patients with albinism. Albinos face a myriad of social and medical issues. Importance of photoprotection, skin cancer surveillance and treatment has been stressed upon in this report.

  3. Enucleation versus plaque irradiation for choroidal melanoma

    International Nuclear Information System (INIS)

    The Collaborative Ocular Melanoma Study (COMS) is an international, multicenter-controlled study. The organization includes an Executive Committee, Steering Committee, 6 Central Units, 32 Clinical Centers, and a Data and Safety Monitoring Committee. Scientifically, the COMS consists of (1) a randomized trial of patients with medium choroidal melanoma treated with enucleation versus iodine-125 plaque irradiation, (2) a randomized trial of patients with large choroidal melanoma treated with enucleation versus preenucleation external beam irradiation and enucleation, and (3) a prospective observational study of patients with small choroidal melanoma to determine whether a randomized trial of treatment is appropriate. In design and conduct of the COMS, special consideration is given to biostatistics and sample size considerations, iodine-125 plaque irradiation of choroidal melanoma, and coordinated ocular melanoma research. Recruitment is in progress. However, the pool of eligible patients is limited and the COMS needs the continued support and cooperation of ophthalmologists throughout the United States and Canada

  4. Non-plaque-induced gingival lesions

    DEFF Research Database (Denmark)

    Holmstrup, P

    1999-01-01

    The origin of gingival inflammation is occasionally different from that of routine plaque-associated gingivitis, and such non-plaque-associated types of gingivitis often present characteristic clinical features. Examples of such forms of gingivitis are specific bacterial, viral, and fungal...... most important of these being Candida species including C. albicans, C. glabrata, C. krusei, C. tropicalis, C. parapsilosis, and C. guillermondii. Gingival histoplasmosis is a granulomatous disease caused by the fungus Histoplasma capsulatum and, as for the other specific infections of gingiva, a...... confirmed diagnosis may require histopathologic examination and/or culture. Atypical gingivitis may also occur as gingival manifestations of dermatological diseases, the most relevant of these being lichen planus, pemphigoid, pemphigus vulgaris, erythema multiforme, and lupus erythematosus. Non...

  5. Pathogenesis of cerebral malaria

    International Nuclear Information System (INIS)

    Full text: Cerebral Malaria (CM) is the most severe complication of malaria and a major cause of death. The mechanisms underlying human CM pathogenesis might be due to mechanical cause, as demonstrated by cytoadherence of parasitised erythrocytes pRB, or to excessive cytokine production by the host in response to Plasmodium falciparum, or a combination of the two together with neuronal injury by malaria toxins. Antibody response, genetic traits and other factors have been proposed to explain why only some episodes have life-threatening complications. The microvascular endothelial cell is a major target of inflammatory cytokines overproduced in infectious diseases. Fatal CM is associated with widespread induction of endothelial activation markers, with significant higher levels of ICAM, VCAM and E-selectin expression on vessels in the brain. 199 patients were admitted at the hospital and were classified with malaria-based neurological disfunctions, such as acute psychosis, ataxia, hallucinations, fever and convulsions, prostration or coma. On a flow chart, 65 of those patients with the most acute syndromes mentioned above, were found to have negative BSN (blood slide), compared to 124 where the BSN showed to be positive. Identically to the 10 other patients from the severe form group, also presented positive BSN. The condition of some of these two subgroup patients (15), will later evolve into a more severe form with acute neurological disfunctions attributed to the cerebral malaria. The interesting aspect in regards to the 65 patients considered as having CM, upon severe manifestations of the disease, show no or little peripheral parasitemia. This fact confirms our experimental conclusion that, in the process of pRB adhesion to the microvessels of the brain, they are sequestered by monocytes and platelets, leading to vessel rupture. This fact could be an explanation of the lower % of circulating pRB and low peripheral parasitemia. There is a relationship between

  6. Apolipoprotein C-II Adopts Distinct Structures in Complex with Micellar and Submicellar Forms of the Amyloid-Inhibiting Lipid-Mimetic Dodecylphosphocholine.

    Science.gov (United States)

    Ryan, Timothy M; Griffin, Michael D W; McGillivray, Duncan J; Knott, Robert B; Wood, Kathleen; Masters, Colin L; Kirby, Nigel; Curtain, Cyril C

    2016-01-01

    The formation of amyloid deposits is a common feature of a broad range of diseases, including atherosclerosis, Alzheimer's disease, and Parkinson's disease. The basis and role of amyloid deposition in the pathogenesis of these diseases is still being defined, however an interesting feature of amyloidogenic proteins is that the majority of the pathologically associated proteins are involved in lipid homeostasis, be it in lipid transport, incorporation into membranes, or the regulation of lipid pathways. Thus, amyloid-forming proteins commonly bind lipids, and lipids are generally involved in the proper folding of these proteins. However, understanding of the basis for these lipid-related aspects of amyloidogenesis is lacking. Thus, we have used the apolipoprotein C-II amyloid model system in conjunction with x-ray and neutron scattering analyses to address this problem. Apolipoprotein C-II is a well-studied model system of systemic amyloid fibril formation, with a clear and well-defined pathway for fibril formation, where the effects of lipid interaction are characterized, particularly for the lipid mimetic dodecylphosphocholine. We show that the micellar state of an inhibitory lipid can have a very significant effect on protein conformation, with micelles stabilizing a particular α-helical structure, whereas submicellar lipids stabilize a very different dimeric, α-helical structure. These results indicate that lipids may have an important role in the development and progression of amyloid-related diseases. PMID:26745412

  7. Helicobacter pylori in Dental Plaque and Saliva

    OpenAIRE

    Kim, Nayoung; Lim, Seon Hee; Lee, Kye Heui; You, Jun Young; Kim, Jung Mogg; Lee, Na Rae; Jung, Hyun Chae; Song, In Sung; Kim, Chung Yong

    2000-01-01

    Background About half of the world population is infected with H. pylori, but the transmission and the source of this infection are still unclear. Recently, dental plaque (DP) and saliva have been implicated as possible sources of H. pylori infection. This study was done to investigate the detection rates of H. pylori in the DP and saliva by use of PCR depending on H. pylori infection state of gastric mucosa. Methods In 46 subjects, gastric H. pylori colonization was evaluated with CLO test, ...

  8. Etanercept in the treatment of plaque psoriasis

    OpenAIRE

    Koo, John

    2009-01-01

    Thao U Nguyen, John KooDepartment of Dermatology, Psoriasis and Skin Treatment Center, University of California, San Francisco, San Francisco, California, USAAbstract: Etanercept is approved for the treatment of moderate to severe plaque psoriasis at a dose of 50 mg twice weekly for 3 months followed by a maintenance dosage of 50 mg weekly thereafter. Clinical studies have shown excellent efficacy, favorable benefit to side-effects ratio, and safe long-term usage. Extensive information on saf...

  9. Hybrid Amyloid Membranes for Continuous Flow Catalysis.

    Science.gov (United States)

    Bolisetty, Sreenath; Arcari, Mario; Adamcik, Jozef; Mezzenga, Raffaele

    2015-12-29

    Amyloid fibrils are promising nanomaterials for technological applications such as biosensors, tissue engineering, drug delivery, and optoelectronics. Here we show that amyloid-metal nanoparticle hybrids can be used both as efficient active materials for wet catalysis and as membranes for continuous flow catalysis applications. Initially, amyloid fibrils generated in vitro from the nontoxic β-lactoglobulin protein act as templates for the synthesis of gold and palladium metal nanoparticles from salt precursors. The resulting hybrids possess catalytic features as demonstrated by evaluating their activity in a model catalytic reaction in water, e.g., the reduction of 4-nitrophenol into 4-aminophenol, with the rate constant of the reduction increasing with the concentration of amyloid-nanoparticle hybrids. Importantly, the same nanoparticles adsorbed onto fibrils surface show improved catalytic efficiency compared to the same unattached particles, pointing at the important role played by the amyloid fibril templates. Then, filter membranes are prepared from the metal nanoparticle-decorated amyloid fibrils by vacuum filtration. The resulting membranes serve as efficient flow catalysis active materials, with a complete catalytic conversion achieved within a single flow passage of a feeding solution through the membrane. PMID:26673736

  10. Islet Amyloid Polypeptide: Structure, Function, and Pathophysiology

    Directory of Open Access Journals (Sweden)

    Rehana Akter

    2016-01-01

    Full Text Available The hormone islet amyloid polypeptide (IAPP, or amylin plays a role in glucose homeostasis but aggregates to form islet amyloid in type-2 diabetes. Islet amyloid formation contributes to β-cell dysfunction and death in the disease and to the failure of islet transplants. Recent work suggests a role for IAPP aggregation in cardiovascular complications of type-2 diabetes and hints at a possible role in type-1 diabetes. The mechanisms of IAPP amyloid formation in vivo or in vitro are not understood and the mechanisms of IAPP induced β-cell death are not fully defined. Activation of the inflammasome, defects in autophagy, ER stress, generation of reactive oxygen species, membrane disruption, and receptor mediated mechanisms have all been proposed to play a role. Open questions in the field include the relative importance of the various mechanisms of β-cell death, the relevance of reductionist biophysical studies to the situation in vivo, the molecular mechanism of amyloid formation in vitro and in vivo, the factors which trigger amyloid formation in type-2 diabetes, the potential role of IAPP in type-1 diabetes, the development of clinically relevant inhibitors of islet amyloidosis toxicity, and the design of soluble, bioactive variants of IAPP for use as adjuncts to insulin therapy.

  11. Alprostadil liposome microsphere preparation stabilizes vascular plaques and inhibits intra-plaque inflammation

    Institute of Scientific and Technical Information of China (English)

    CHEN Li; CHENG Wen-li; WANG Yong; KE Yuan-nan; FAN Shu-ying; PAN Lin; GUO Yan-ru; LI Hong; GUO Jian

    2012-01-01

    Background Vulnerable plaques play an important role in the onset of sudden cardiac events and strokes.How to stabilize vulnerable plaques is still a challenge to medical science.Alprostadil is a biologically active substance with strong activity on vessel.Our study assessed the stabilizing effects of an alprostadil liposome microsphere preparation (ALMP) on vulnerable plaques in the brachiocephalic artery of apolipoprotein E (Apo E) knockout mice.Methods Seventy-two male Apo E-knockout mice were fed a high-fat diet beginning at eight weeks of age.At week 17,they were divided randomly into groups for treatment with a high dose (3.6 μg · kg-1 · d-1) or low dose (1.8 μg · kg-1 · d-1) of an ALMP,or 0.2 ml/d normal saline (control group).The drug was administered using a micro-capsule pump.Twenty weeks after drug administration,pathological changes in the vulnerable plaques within the brachiocephalic artery were assessed,and levels of anti-mouse monocyte/macrophage monoclonal antibody (MOMA-2) and superoxide anions in the plaques were detected using immunofluorescence.The soluble intercellular adhesion molecule-1 (ICAM-1) expression was measured by ELISA,and the expression of matrix metalloproteinase-9 (MMP-9) and CD40 mRNA was measured using RT-PCR.Thrombospindin-1 (TSP-1) expression was detected using Western blotting.Results Compared with the control group,ALMP treatment significantly reduced the plaque area in the brachiocephalic artery (P <0.01),significantly lowered the contents of the lipid core (P <0.01),significantly reduced the number of ruptured fibrous caps (P <0.05),and increased the thickness of the fibrous cap and significantly reduced the incidence of intra-plaque hemorrhage (P <0.05).ALMP treatment significantly reduced the expression of MOMA-2,superoxide anion,MMP-9,ICAM-1 and CD40 in the plaques (P <0.01),decreased plasma ICAM-1 expression (P <0.01),and increased the expression of TSP-1.Conclusions Treatment with ALMP can stabilize

  12. Highlights in pathogenesis of vitiligo.

    Science.gov (United States)

    Mohammed, Ghada F; Gomaa, Amal Ha; Al-Dhubaibi, Mohammed Saleh

    2015-03-16

    Vitiligo is a common pigmentary disorder. Many studies across decades and all over the world have attempted to illustrate the pathogenesis behind it; however, the pathogenesis of vitiligo remains elusive. This review article, we present the findings behind the most and updated theories behind this psychologically debilitating and disfiguring disease. The discussion begun with the role of genetic predisposition followed by neural theory first proposed in the 1950s. We highlight the autoimmune hypothesis, followed by the reactive oxygen species model, zinc-α2-glycoprotein deficiency hypothesis, viral theory, intrinsic theory and biochemical, molecular and cellular alterations accounting for loss of functioning melanocytes in vitiligo. Many theories were elaborated to clarify vitiligo pathogenesis. It is a multifactorial disease involving the interplay of several factors. Future research is needed to clarify the interaction of these factors for better understanding of vitiligo pathogenesis and subsequent successful treatment. PMID:25789295

  13. Optimization of 125I ophthalmic plaque brachytherapy

    International Nuclear Information System (INIS)

    Episcleral plaques containing 125I sources are often used in the treatment of ocular melanoma. Within four years post-treatment, however, the majority of patients experience some visual loss due to radiation retinopathy. The high incidence of late complications suggests that careful treatment optimization may lead to improved outcome. The goal of optimization would be to reduce the magnitude of vision-limiting complications without compromising tumor control. We have developed a three-dimensional computer model for ophthalmic plaque therapy which permits us to explore the potential of various optimization strategies. One simple strategy which shows promise is to maximize the ratio of dose to the tumor apex (T) compared to dose to the macula (M). By modifying the parameters of source location, activity distribution, source orientation, and shielding we find that the calculated T:M ratio can be varied by a factor of 2 for a common plaque design and posterior tumor location. Margins and dose to the tumor volume remain essentially unchanged

  14. Cataractogenesis after Cobalt-60 eye plaque radiotherapy

    International Nuclear Information System (INIS)

    This study was designed to estimate the actuarial incidence of typical postirradiation cataracts and to identify prognostic factors related to their development in melanoma-containing eyes treated by Cobalt-60 plaque radiotherapy. A special interest was the impact of calculated radiation dose and dose-rate to the lens. The authors evaluated the actuarial occurrence of post-irradiation cataract in 365 patients with primary posterior uveal melanoma treated by Cobalt-60 plaque radiotherapy between 1976 and 1986. Only 22% (S.E. = 4.6%) of the patients who received a total dose of 6 to 20 Gy at the center of the lens developed a visually significant cataract attributable to the radiation within 5 years after treatment. Using multivariate Cox proportional hazards modeling, the authors identified thickness of the tumor, location of the tumor's anterior margin relative to the equatorward and the ora serrata, and diameter of the eye plaque used as the best combination of covariables for predicting length of time until development of cataract. Surprisingly, the dose of radiation delivered to the lens, which was strongly correlated to all of these covariables, was not a significant predictive factor in multivariate analysis. The results suggest that success of efforts to decrease the occurrence rate of post-irradiation cataracts by better treatment planning might be limited in patients with posterior uveal melanoma. 21 refs., 2 figs., 5 tabs

  15. Molecular mechanisms of rosacea pathogenesis

    Directory of Open Access Journals (Sweden)

    Davydova A.M.

    2013-09-01

    Full Text Available The article presents possible molecular mechanisms for rosacea pathogenesis from current domestic and foreign clinical observations and laboratory research: regulation and expression defects of antimicrobial peptides, vascular endothelial growth factor, the effect of serine proteases, oxidative stress, reactive oxygen species and ferritin on the occurrence and course of rosacea. New developments in molecular biology and genetics are advanced for researching the interaction of multiple factors involved in rosacea pathogenesis, as well as providing the bases for potentially new therapies.

  16. Inflammation and Atherosclerosis: Current Pathogenesis

    OpenAIRE

    Anna Meiliana; Andi Wijaya

    2012-01-01

    BACKGROUND: The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. CONTENT: Chronic inflammation is recognized as a major driving force in atherogenesis. The sites of atherosclerotic plaque development in the arterial wall are characterized by cholesterol accumulation and infiltration of peripheral blood monocytes, which gradually differentiate into macrophages. Cholesterol crystals, the common consti...

  17. Fatal transmissible amyloid encephalopathy: a new type of prion disease associated with lack of prion protein membrane anchoring.

    Directory of Open Access Journals (Sweden)

    Bruce Chesebro

    2010-03-01

    Full Text Available Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres. PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen, a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI. Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

  18. Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity

    Science.gov (United States)

    Cheng, Pin-Nan; Liu, Cong; Zhao, Minglei; Eisenberg, David; Nowick, James S.

    2012-11-01

    The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β2-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.

  19. Serum amyloid A1: Structure, function and gene polymorphism.

    Science.gov (United States)

    Sun, Lei; Ye, Richard D

    2016-05-25

    Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1-SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins. PMID:26945629

  20. Islet amyloid polypeptide-induced membrane leakage involves uptake of lipids by forming amyloid fibers.

    Science.gov (United States)

    Sparr, Emma; Engel, Maarten F M; Sakharov, Dmitri V; Sprong, Mariette; Jacobs, Jet; de Kruijff, Ben; Höppener, Jo W M; Killian, J Antoinette

    2004-11-01

    Fibril formation of islet amyloid polypeptide (IAPP) is associated with cell death of the insulin-producing pancreatic beta-cells in patients with Type 2 Diabetes Mellitus. A likely cause for the cytotoxicity of human IAPP is that it destroys the barrier properties of the cell membrane. Here, we show by fluorescence confocal microscopy on lipid vesicles that the process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits. No membrane interaction was observed when preformed fibrils were used. It is proposed that lipid uptake from the cell membrane is responsible for amyloid-induced membrane damage and that this represents a general mechanism underlying the cytotoxicity of amyloid forming proteins. PMID:15527771

  1. Correlation of plaque nitric oxide levels with plaque Streptococcus mutans, plaque pH and decayed, missing and filled teeth index of children of different age groups

    Directory of Open Access Journals (Sweden)

    Sawinderjit Saini

    2016-01-01

    Full Text Available Context: Dental plaque is considered one of the most important etiological factors for dental caries. Nitrate and Nitrite levels in saliva are considered protective against oral and gastrointestinal disease. Plaque nitric oxide (NO levels and its role in dental caries has not be explored in the literature. Aim: Determine the correlation of the plaque nitric oxide (NO with dental caries in vivo. Materials and Method: 75 healthy children between ages of 3-15 years were selected. The age, state of dentition and the level of caries in all individuals were determined by the same examiner, using DMFT/deft index. The plaque samples collected were subjected to nitric oxide estimation, streptococcus mutans count and pH for correlation. Statistical Analysis Used: SPSS computer based software was used for descriptive data analysis. ANOVA one way analysis and Karl pearson′s correlation was carried out. Results and Conclusion: Statistically significant relationship was observed between plaque nitric oxide and dental caries in all age groups. Similarly, significant correlation of nitric oxide was found in relation to plaque streptococcus mutans and plaque pH. Thus concluded, plaque nitric oxide can be considered as a risk assessment tool for prediction of dental caries.

  2. The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease.

    Science.gov (United States)

    Walker, Lary C; Schelle, Juliane; Jucker, Mathias

    2016-01-01

    Since the discovery that prion diseases can be transmitted to experimental animals by inoculation with afflicted brain matter, researchers have speculated that the brains of patients suffering from other neurodegenerative diseases might also harbor causative agents with transmissible properties. Foremost among these disorders is Alzheimer's disease (AD), the most common cause of dementia in the elderly. A growing body of research supports the concept that the pathogenesis of AD is initiated and sustained by the endogenous, seeded misfolding and aggregation of the protein fragment amyloid-β (Aβ). At the molecular level, this mechanism of nucleated protein self-assembly is virtually identical to that of prions consisting of the prion protein (PrP). The formation, propagation, and spread of Aβ seeds within the brain can thus be considered a fundamental feature of AD pathogenesis. PMID:27270558

  3. A novel phosphodiesterase-5 Inhibitor: Yonkenafil modulates neurogenesis, gliosis to improve cognitive function and ameliorates amyloid burden in an APP/PS1 transgenic mice model.

    Science.gov (United States)

    Zhu, Lei; Yang, Jing-yu; Xue, Xue; Dong, Ying-xu; Liu, Yang; Miao, Feng-rong; Wang, Yong-feng; Xue, Hong; Wu, Chun-fu

    2015-09-01

    In Alzheimer's disease (AD), activated microglia invade and surround β-amyloid plaques, possibly contributing to the aggregation of amyloid β (Aβ), which affect the survival of neurons and lead to memory loss. Phosphodiesterase-5 (PDE-5) inhibitors have recently been shown a potential therapeutic effect on AD. In this study, the effects of yonkenafil (yonk), a novel PDE-5 inhibitor, on cognitive behaviors as well as the pathological features in transgenic AD mice were investigated. Seven-month-old APP/PS1 transgenic mice were treated with yonk (2, 6, or 18 mg/kg, intraperitoneal injection (i.p.)) or sildenafil (sild) (6 mg/kg, i.p.) daily for 3 months and then behavioral tests were performed. The results demonstrated that yonk improved nesting-building ability, ameliorated working memory deficits in the Y-maze tasks, and significantly improved learning and memory function in the Morris water maze (MWM) tasks. In addition, yonk reduced the area of Aβ plaques, and inhibited over-activation of microglia and astrocytes. Furthermore, yonk increased neurogenesis in the dentate granule brain region of APP/PS1 mice, indicated by increased BrdU(+)/NeuN(+) and BrdU(+)/DCX(+) cells compared to vehicle-treated transgenic mice. These results suggest that yonk could rescue cognitive deficits by ameliorated amyloid burden through regulating APP processing, inhibited the over-activation of microglia and astrocytes as well as restored neurogenesis. PMID:26200391

  4. Micro-analysis of plaque fluid from single-site fasted plaque

    International Nuclear Information System (INIS)

    Despite the site-specific nature of caries, nearly all data on the concentration of ions relevant to the level of saturation of plaque fluid with respect to calcium phosphate minerals or enamel are from studies that used pooled samples. A procedure is described for the collection and analysis of inorganic ions relevant to these saturation levels in plaque fluid samples collected from a single surface on a single tooth. Various methods for examining data obtained by this procedure are described, and a mathematical procedure employing potential plots is recommended

  5. Contemporary treatment of amyloid heart disease.

    Science.gov (United States)

    Palecek, Tomas; Fikrle, Michal; Nemecek, Eduard; Bauerova, Lenka; Kuchynka, Petr; Louch, William E; Spicka, Ivan; Rysava, Romana

    2015-01-01

    The amyloidoses represent a group of diseases characterized by extracellular deposition of abnormal protein, amyloid, which is formed by insoluble extracellular fibrils in β-pleated sheets. Although cardiac involvement may occur in all types of amyloidoses, clinically relevant amyloid cardiomyopathy is a typical feature of AL amyloidosis and transthyretin-related amyloidoses. Congestive heart failure represents the commonest manifestation of amyloid heart disease. Noninvasive imaging techniques, especially echocardiography and cardiac magnetic resonance, play a major role in the diagnosis of amyloid cardiomyopathy; however, histological confirmation and exact typing of amyloid deposits is necessary whether in extracardiac location or directly in the myocardium. Early diagnosis of amyloid heart disease is of utmost importance as the presence and especially the severity of cardiac involvement generally drives the prognosis of affected subjects and plays a major role in determining the intensity of specific treatment, namely in AL amyloidosis. The management of patients with amyloid heart disease is complex. Loop diuretics together with aldosterone antagonists represent the basis for influencing signs of congestion. In AL amyloidosis, high-dose chemotherapy followed by autologous stem cell transplantation is generally considered to be a front-line treatment option, if the disease is diagnosed at its early stage. The combination of mephalan with dexamethasone has been the standard therapy for severely affected individuals; however, the combinations with several novel agents including immunomodulatory drugs and bortezomibe have been tested in clinical trials with promising results. New therapeutic substances with the potential to slow or even stop the progression of transthyretin-related amyloidosis are also extensively studied. PMID:25483951

  6. Le médicament du mois. L'étanercept (Enbrel) pour le traitement du psoriasis en plaques modéré a sévère.

    OpenAIRE

    Franchimont, Claudine; Pierard, Gérald

    2006-01-01

    Etanercept (Enbrel) is a soluble tumour necrosis factor (TNF) receptor drug. By this mechanism, it inhibits the effects of TNF-alpha involved in the pathogenesis of psoriasis. Enbrel is approved for the treatment of moderate to severe chronic plaque psoriasis, and also for psoriatic arthritis.

  7. Thermodynamic description of Beta amyloid formation using physicochemical scales and fractal bioinformatic scales.

    Science.gov (United States)

    Phillips, J C

    2015-05-20

    Protein function depends on both protein structure and amino acid (aa) sequence. Here we show that modular features of both structure and function can be quantified economically from the aa sequences alone for the small (40,42 aa) plaque-forming (aggregative) amyloid beta fragments. Some edge and center features of the fragments are predicted. Bioinformatic scales based on β strand formation propensities and the thermodynamically second order fractal hydropathicity scale based on evolutionary optimization (self-organized criticality) are contrasted with the standard first order physicochemical scale based on complete protein (water-air) unfolding. The results are consistent with previous studies of these physicochemical factors that show that aggregative properties, even of beta fragments, are driven primarily by near-equilibrium hydropathic forces. PMID:25702750

  8. Oligomer stability of Amyloid- β (A β) 25-35: A Dissipative Particle Dynamics study

    Science.gov (United States)

    Pivkin, Igor; Peter, Emanuel

    Alzheimer's disease is strongly associated with an accumulation of Amyloid- β (A β) peptide plaques in the human brain. A β is a 43 residues long intrinsically disordered peptide and has a strong tendency to form aggregates. Evidence accumulates that A β acts toxic to the neurons in the brain through the formation of small soluble oligomers. A β 25-35 is the smallest fragment of A β which still retains its toxicity and its ability to form extended fibrils. In this talk we will present the results from simulations of aggregation of up to 100 A β 25-35 peptides using a novel polarizable coarse-grained protein model in combination with Dissipative Particle Dynamics.

  9. Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

    Directory of Open Access Journals (Sweden)

    Todd J. Eckroat

    2013-05-01

    Full Text Available The number of people suffering from Alzheimer’s disease (AD is expected to increase dramatically in the coming years, placing a huge burden on society. Current treatments for AD leave much to be desired, and numerous research efforts around the globe are focused on developing improved therapeutics. In addition, current diagnostic tools for AD rely largely on subjective cognitive assessment rather than on identification of pathophysiological changes associated with disease onset and progression. These facts have led to numerous efforts to develop chemical probes to detect pathophysiological hallmarks of AD, such as amyloidplaques, for diagnosis and monitoring of therapeutic efficacy. This review provides a survey of chemical probes developed to date for AD with emphasis on synthetic methodologies and structure–activity relationships with regards to affinity for target and brain kinetics. Several probes discussed herein show particularly promising results and will be of immense value moving forward in the fight against AD.

  10. Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

    Directory of Open Access Journals (Sweden)

    Gerald A Dienel

    2010-08-01

    Full Text Available Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (1 μmol/l for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50–70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue, NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5–14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10–2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system.

  11. Broad neutralization of calcium-permeable amyloid pore channels with a chimeric Alzheimer/Parkinson peptide targeting brain gangliosides.

    Science.gov (United States)

    Di Scala, Coralie; Yahi, Nouara; Flores, Alessandra; Boutemeur, Sonia; Kourdougli, Nazim; Chahinian, Henri; Fantini, Jacques

    2016-02-01

    Growing evidence supports a role for brain gangliosides in the pathogenesis of neurodegenerative diseases including Alzheimer's and Parkinson's. Recently we deciphered the ganglioside-recognition code controlling specific ganglioside binding to Alzheimer's β-amyloid (Aβ1-42) peptide and Parkinson's disease-associated protein α-synuclein. Cracking this code allowed us to engineer a short chimeric Aβ/α-synuclein peptide that recognizes all brain gangliosides. Here we show that ganglioside-deprived neural cells do no longer sustain the formation of zinc-sensitive amyloid pore channels induced by either Aβ1-42 or α-synuclein, as assessed by single-cell Ca(2+) fluorescence microscopy. Thus, amyloid channel formation, now considered a key step in neurodegeneration, is a ganglioside-dependent process. Nanomolar concentrations of chimeric peptide competitively inhibited amyloid pore formation induced by Aβ1-42 or α-synuclein in cultured neural cells. Moreover, this peptide abrogated the intracellular calcium increases induced by Parkinson's-associated mutant forms of α-synuclein (A30P, E46K and A53T). The chimeric peptide also prevented the deleterious effects of Aβ1-42 on synaptic vesicle trafficking and decreased the Aβ1-42-induced impairment of spontaneous activity in rat hippocampal slices. Taken together, these data show that the chimeric peptide has broad anti-amyloid pore activity, suggesting that a common therapeutic strategy based on the prevention of amyloid-ganglioside interactions is a reachable goal for both Alzheimer's and Parkinson's diseases. PMID:26655601

  12. Disruption of zinc homeostasis and the pathogenesis of senile dementia.

    Science.gov (United States)

    Kawahara, Masahiro; Mizuno, Dai; Koyama, Hironari; Konoha, Keiko; Ohkawara, Susumu; Sadakane, Yutaka

    2014-02-01

    Zinc (Zn) is an essential trace element that is abundantly present in the brain. Although Zn plays crucial roles in learning and memory, numerous studies have indicated that the disruption of Zn homeostasis, namely both depletion and excess Zn, causes severe damage to neurons and is linked with various neurodegenerative diseases including Alzheimer's disease and vascular dementia. Here, we review the current understanding of the role of Zn in the pathogenesis of these neurodegenerative diseases. Based on our findings and other numerous studies, Zn acts as a contributor to Alzheimer's disease in the oligomerization, and as a protector in the neurotoxicity of Alzheimer's β-amyloid protein. Furthermore, Zn plays a central role in ischemia-induced neuronal death and the pathogenesis of vascular dementia. Involvement of Ca(2+) dyshomeostasis and endoplasmic reticulum (ER) stress in the mechanism of Zn-induced neurotoxicity are suggested. We also discuss the possible role of carnosine (β-alanyl histidine), a dipeptide that is present in the brain, as a protective substance for neuronal injury. PMID:24247360

  13. Synthesis of fluorescent-maghemite nanoparticles as multimodal imaging agents for amyloid-beta fibrils detection and removal by a magnetic field.

    Science.gov (United States)

    Skaat, Hadas; Margel, Shlomo

    2009-09-01

    Early diagnosis in Alzheimer's disease (AD), before the onset of marked clinical symptoms, is critical in preventing the irreversible neuronal damage that eventually leads to dementia and ultimately death. Therefore, there is an urgent need for in vivo imaging agents, which are valuable as specific biomarkers to demonstrate the location and density of amyloid plaques in the living human brain. The present manuscript describes a novel method for selective marking of Abeta(40) fibrils by non-fluorescent gamma-Fe(2)O(3) and fluorescent-magnetic gamma-Fe(2)O(3)-rhodamine or gamma-Fe(2)O(3)-Congo red nanoparticles, and the complete removal of the magnetized fibrils from the aqueous continuous phase by a magnetic field. These fluorescent-maghemite nanoparticles as multimodal imaging agents have a great advantage due to the combination of the magnetic and fluorescence imaging into one nanostructured system. This hybrid system, which selectively marks Abeta(40) fibrils, might enable the early detection of plaques using both MRI and fluorescence microscopy, and therefore may be applied in in vivo AD diagnosis studies. These fluorescent-magnetic nanoparticles may also be useful as selective biomarkers to detect the location and the removal of other amyloid plaques derived from different amyloidogenic proteins that lead to neurodegenerative diseases, e.g., Parkinson's, Huntington's, mad cow, and prion diseases. PMID:19559008

  14. Dosimetric Benefit of a New Ophthalmic Radiation Plaque

    Energy Technology Data Exchange (ETDEWEB)

    Marwaha, Gaurav, E-mail: marwahg2@ccf.org [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Wilkinson, Allan [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Bena, James [Department of Quantitative Health Sciences, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Macklis, Roger [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States); Singh, Arun D. [Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio (United States); Cleveland Clinic Foundation, Cleveland, Ohio (United States)

    2012-12-01

    Purpose: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. Methods and Materials: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. Results: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], -2.8 to -1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, -20.16 to -15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. Conclusion: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

  15. Expression of NPP1 is regulated during atheromatous plaque calcification

    OpenAIRE

    Nitschke, Yvonne; Hartmann, Simone; Torsello, Giovanni; Horstmann, Rüdiger; Seifarth, Harald; Weissen-Plenz, Gabriele; Rutsch, Frank

    2009-01-01

    Abstract Mutations of the ENPP1 gene encoding ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) are associated with medial calcification in infancy. While the inhibitory role of matrix proteins such as osteopontin (OPN) with respect to atherosclerotic plaque calcification has been established, the role of NPP1 in plaque calcification is not known. We assessed the degree of plaque calcification (computed tomography), NPP1 and OPN localization (immunohistochemistry) and expression (RT-...

  16. Helicobacter pylori in the dental plaque of healthy Saudis

    OpenAIRE

    Contractor Qais; Tahir Mohammed; Naseem Shahzad; Ahmad Shamweel

    1998-01-01

    The objective of this study is to determine the presence of Helicobacter pylori in the dental plaque of healthy Saudis and its relation to dental care. One hundred randomly selected healthy Saudis attending the dental clinic were assessed for oral hygiene and periodontal disease by dental examination. Information about the use of toothpaste, chewing stick, smoking and dentures was obtained. Samples of dental plaque were collected after scoring it according to the plaque index. Presence of H. ...

  17. Multimodality imaging of carotid atherosclerotic plaque: Going beyond stenosis

    OpenAIRE

    Divyata Hingwala; Chandrasekharan Kesavadas; Sylaja, Padmavathy N; Bejoy Thomas; Tirur Raman Kapilamoorthy

    2013-01-01

    Apart from the degree of stenosis, the morphology of carotid atherosclerotic plaques and presence of neovascularization are important factors that may help to evaluate the risk and ′vulnerability′ of plaques and may also influence the choice of treatment. In this article, we aim to describe the techniques and imaging findings on CTA, high resolution MRI and contrast enhanced ultrasound in the evaluation of carotid atherosclerotic plaques. We also discuss a few representative cases from our in...

  18. Cell surface hydrophobicity of dental plaque microorganisms in situ.

    OpenAIRE

    Rosenberg, M.; Judes, H; Weiss, E

    1983-01-01

    The cell surface hydrophobicity of bacteria obtained directly from human tooth surfaces was assayed by measuring their adherence to liquid hydrocarbons. Fresh samples of supragingival dental plaque were washed and dispersed in buffer. Adherence of the plaque microorganisms to hexadecane, octane, and xylene was tested turbidimetrically and by direct microscopic observation. The results clearly show that the vast majority of bacteria comprising dental plaque exhibit pronounced cell surface hydr...

  19. Prophylaxis for infective endocarditis: antibiotic sensitivity of dental plaque.

    OpenAIRE

    MacFarlane, T W; McGowan, D. A.; Hunter, K; MacKenzie, D.

    1983-01-01

    The antibiotic sensitivity pattern of bacteria isolated from bacteraemia after dental extraction was compared with that of bacteria isolated from dental plaque samples from the same patient. The results supported the current practice of using penicillin and erythromycin empirically for prophylaxis. The prediction of the most appropriate antibiotic for prophylaxis using dental plaque samples was most accurate when the minimum inhibitory concentration (MIC) of plaque isolates were used. It appe...

  20. Dosimetric Benefit of a New Ophthalmic Radiation Plaque

    International Nuclear Information System (INIS)

    Purpose: To determine whether the computed dosimetry of a new ophthalmic plaque, EP917, when compared with the standard Collaborative Ocular Melanoma Study (COMS) plaques, could reduce radiation exposure to vision critical structures of the eye. Methods and Materials: One hundred consecutive patients with uveal melanoma treated with COMS radiation plaques between 2007 and 2010 were included in this study. These treatment plans were generated with the use of Bebig Plaque Simulator treatment-planning software, both for COMS plaques and for EP917 plaques using I-125. Dose distributions were calculated for a prescription of 85 Gy to the tumor apex. Doses to the optic disc, opposite retina, lens, and macula were obtained, and differences between the 2 groups were analyzed by standard parametric methods. Results: When compared with the COMS plaques, the EP917 plaques used fewer radiation seeds by an average difference of 1.94 (P<.001; 95% confidence interval [CI], −2.8 to −1.06) and required less total strength of radiation sources by an average of 17.74 U (air kerma units) (P<.001; 95% CI, −20.16 to −15.32). The total radiation doses delivered to the optic disc, opposite retina, and macula were significantly less by 4.57 Gy, 0.50 Gy, and 11.18 Gy, respectively, with the EP917 plaques vs the COMS plaques. Conclusion: EP917 plaques deliver less overall radiation exposure to critical vision structures than COMS treatment plaques while still delivering the same total therapeutic dose to the tumor.

  1. Extrahepatic production of acute phase serum amyloid A

    OpenAIRE

    Upragarin, N.; Landman, W.J.M.; Gaastra, W; Gruys, E.

    2005-01-01

    Amyloidosis is a group of diseases characterized by the extracellular deposition of protein that contains non-branching, straight fibrils on electron microscopy (amyloid fibrils) that have a high content of ß-pleated sheet conformation. Various biochemically distinct proteins can undergo transformation into amyloid fibrils. The precursor protein of amyloid protein A (AA) is the acute phase protein serum amyloid A (SAA). The concentration of SAA in plasma increa...

  2. STIMULATED PLATELETS RELEASE AMYLOID β–PROTEIN PRECURSOR

    OpenAIRE

    Cole, Gregory M.; Galasko, Douglas; Shapiro, I. Paul; Saitoh, Tsunao

    1990-01-01

    Human platelets can be stimulated by thrombin or ionomycin to secrete soluble truncated amyloid β–protein precursor and particulate membrane fragments which contain C-terminal and N-terminal immunoreactive amyloid β–protein precursor. This suggests a possible circulating source of β–protein in serum which may play a role in the formation of amyloid deposits. The release of soluble amyloid β-protein precursor could be involved in normal platelet physiology.

  3. Oral biofilm models for mechanical plaque removal.

    Science.gov (United States)

    Verkaik, Martinus J; Busscher, Henk J; Rustema-Abbing, Minie; Slomp, Anje M; Abbas, Frank; van der Mei, Henny C

    2010-08-01

    In vitro plaque removal studies require biofilm models that resemble in vivo dental plaque. Here, we compare contact and non-contact removal of single and dual-species biofilms as well as of biofilms grown from human whole saliva in vitro using different biofilm models. Bacteria were adhered to a salivary pellicle for 2 h or grown after adhesion for 16 h, after which, their removal was evaluated. In a contact mode, no differences were observed between the manual, rotating, or sonic brushing; and removal was on average 39%, 84%, and 95% for Streptococcus mutans, Streptococcus oralis, and Actinomyces naeslundii, respectively, and 90% and 54% for the dual- and multi-species biofilms, respectively. However, in a non-contact mode, rotating and sonic brushes still removed considerable numbers of bacteria (24-40%), while the manual brush as a control (5-11%) did not. Single A. naeslundii and dual-species (A. naeslundii and S. oralis) biofilms were more difficult to remove after 16 h growth than after 2 h adhesion (on average, 62% and 93% for 16- and 2-h-old biofilms, respectively), while in contrast, biofilms grown from whole saliva were easier to remove (97% after 16 h and 54% after 2 h of growth). Considering the strong adhesion of dual-species biofilms and their easier more reproducible growth compared with biofilms grown from whole saliva, dual-species biofilms of A. naeslundii and S. oralis are suggested to be preferred for use in mechanical plaque removal studies in vitro. PMID:19565279

  4. Dental plaque - associated infections and antibacterial oral hygiene products.

    Science.gov (United States)

    Verran, J

    1991-02-01

    Synopsis Dental plaque accumulates on hard non-shedding surfaces such as teeth, dentures and orthodontic appliances. This accumulation is facilitated by the absence of adequate oral hygiene procedures. The term 'plaque' describes a mass of microorganisms embedded in an organic matrix of host and microbial origin. In addition to the aesthetic desirability of 'clean teeth, healthy gums and fresh breath' associated with the absence of plaque, obvious consequences of the presence of plaque include tooth decay (dental caries), gingivitis and periodontal (gum) disease and denture associated problems. Thus the prevention of plaque formation, the reduction of plaque accumulation and the effective removal of plaque are considerations of the cosmetic and health professions alike. There are many oral hygiene products available to the general public - toothpastes, mouthwashes, denture cleaners, and, more recently, chewing gums and novel mouthwashes. Several of these products have antimicrobial components. This paper reviews the microbiology of plaque and plaque associated problems, and surveys the type of products currently available for maintenance of good oral hygiene. Potential areas for future development are also explored. PMID:19291039

  5. Association of Streptococcus with Plaque Type of Psoriasis

    Directory of Open Access Journals (Sweden)

    Mohammad Akram Hossain

    2015-05-01

    Full Text Available Background: Guttate psoriasis has a well-known association with streptococcal throat infections, but the effects of these infections in patients with chronic plaque type of psoriasis remains to be evaluated. In Bangladesh several studies were done on psoriasis but no data about association between streptococcal throat infection and plaque type psoriasis are available so far. Considering the co-morbidities of psoriasis patients, it might be justifiable to find out the events that provoke the initiation or exacerbation of psoriatic disease process. Objective: To observe the association of streptococcus with plaque type of psoriasis. Materials and Methods: This observational study was conducted in the department of Dermatology and Venereology, Bangabandhu Sheikh Mujib Medical University, Dhaka. Forty seven patients clinically and histopathologically diagnosed as having plaque psoriasis were selected as cases and patients with skin diseases other than psoriasis were selected as controls. Results: In this study majority of subjects (55% were diagnosed as chronic plaque psoriasis. Among the subjects with guttate flare of chronic plaque psoriasis 64.2% gave a positive history of sore throat. ASO titer was raised (>200 IU/mL in 28 (59.5% patients of chronic plaque psoriasis and 7 (17.9% patients of non-psoriatic respondents. The difference between two groups was significant (p0.05. Conclusion: This study shows that streptococcal throat infections are associated with plaque psoriasis and early treatment of throat infections may be beneficial for plaque type of psoriasis patients.

  6. Isolation of Helicobacter pylori from dental plaque: A microbiological study

    OpenAIRE

    Sudhakar, Uma; Anusuya, C. N.; Ramakrishnan, T.; Vijayalakshmi, R.

    2008-01-01

    Aim The aim of our study was to isolate H. pylori from dental plaque in gastric and duodenal ulcer patients and compare it with dental plaque of healthy subjects. Materials and Methods Fifty patients in the age range of 25-50 years who were endoscopically proven cases of duodenal and gastric ulcer were chosen. H. pylorus was isolated from the dental plaque of these patients using culture method and rapid urease test (RUT). It was compared with the dental plaque from control group (25 students...

  7. The novel amyloid-beta peptide aptamer inhibits intracellular amyloid-beta peptide toxicity

    Institute of Scientific and Technical Information of China (English)

    Xu Wang; Yi Yang; Mingyue Jia; Chi Ma; Mingyu Wang; Lihe Che; Yu Yang; Jiang Wu

    2013-01-01

    Amyloid β peptide binding alcohol dehydrogenase (ABAD) decoy peptide (DP) can competitively antagonize binding of amyloid β peptide to ABAD and inhibit the cytotoxic effects of amyloid β peptide. Based on peptide aptamers, the present study inserted ABAD-DP into the disulfide bond of human thioredoxin (TRX) using molecular cloning technique to construct a fusion gene that can express the TRX1-ABAD-DP-TRX2 aptamer. Moreover, adeno-associated virus was used to allow its stable expression. Immunofluorescent staining revealed the co-expression of the transduced fusion gene TRX1-ABAD-DP-TRX2 and amyloid β peptide in NIH-3T3 cells, indicating that the TRX1-ABAD-DP-TRX2 aptamer can bind amyloid β peptide within cells. In addition, cell morphology and MTT results suggested that TRX1-ABAD-DP-TRX2 attenuated amyloid β peptide-induced SH-SY5Y cell injury and improved cell viability. These findings confirmed the possibility of constructing TRX-based peptide aptamer using ABAD-DP. Moreover, TRX1-ABAD-DP-TRX2 inhibited the cytotoxic effect of amyloid β peptide.

  8. The Cotton Rat (Sigmodon hispidus) Is a Permissive Small Animal Model of Human Metapneumovirus Infection, Pathogenesis, and Protective Immunity

    OpenAIRE

    Williams, John V.; Tollefson, Sharon J.; Johnson, Joyce E.; Crowe, James E.

    2005-01-01

    Human metapneumovirus (hMPV) is a newly described paramyxovirus that is an important cause of acute respiratory tract disease. We undertook to develop a small animal model of hMPV infection, pathogenesis, and protection. Hamsters, guinea pigs, cotton rats, and nine inbred strains of mice were inoculated intranasally with hMPV. The animals were sacrificed, and nasal and lung tissue virus yields were determined by plaque titration. None of the animals exhibited respiratory symptoms. The quantit...

  9. Multiscale Molecular Dynamics Simulations of Beta-Amyloid Interactions with Neurons

    Science.gov (United States)

    Qiu, Liming; Vaughn, Mark; Cheng, Kelvin

    2012-10-01

    Early events of human beta-amyloid protein interactions with cholesterol-containing membranes are critical to understanding the pathogenesis of Alzheimer's disease (AD) and to exploring new therapeutic interventions of AD. Atomistic molecular dynamics (AMD) simulations have been extensively used to study the protein-lipid interaction at high atomic resolutions. However, traditional MD simulations are not efficient in sampling the phase space of complex lipid/protein systems with rugged free energy landscapes. Meanwhile, coarse-grained MD (CGD) simulations are efficient in the phase space sampling but suffered from low spatial resolutions and from the fact that the energy landscapes are not identical to those of the AMD. Here, a multiscale approach was employed to simulate the protein-lipid interactions of beta-amyloid upon its release from proteolysis residing in the neuronal membranes. We utilized a forward (AMD to CGD) and reverse (CGD-AMD) strategy to explore new transmembrane and surface protein configuration and evaluate the stabilization mechanisms by measuring the residue-specific protein-lipid or protein conformations. The detailed molecular interactions revealed in this multiscale MD approach will provide new insights into understanding the early molecular events leading to the pathogenesis of AD.

  10. Estrogen stimulates release of secreted amyloid precursor protein from primary rat cortical neurons via protein kinase C pathway

    Institute of Scientific and Technical Information of China (English)

    Sun ZHANG; Ying HUANG; Yi-chun ZHU; Tai YAO

    2005-01-01

    Aim: To investigate the mechanism of the action of estrogen, which stimulates the release of secreted amyloid precursor protein α (sAPPα) and decreases the gen eration of amyloid-β protein (Aβ), a dominant component in senile plaques in the brains of Alzheimer's disease patients. Methods: Experiments were carried out inprimary rat cortical neurons, and Western blot was used to detect sAPPα in aculture medium and the total amount of cellular amyloid precursor protein (APP) in neurons. Results: 17β-Estradiol (but not 17α-estradiol) and β-estradiol 6-(Ocarboxymethyl) oxime: BSA increased the secretion of sAPPα and this effect was blocked by protein kinase C (PKC) inhibitor calphostin C, but not by the classical estrogen receptor antagonist ICI 182,780. Meanwhile, 17β-estradiol did not alter the synthesis of cellular APP. Conclusion: The effect of 17β-estradiol on sAPPα secretion is likely mediated through the membrane binding sites, and needs molecular configuration specificity of the ligand. Furthermore, the action of the PKC dependent pathway might be involved in estrogen-induced sAPPα secretion.

  11. Determining the Effect of Aluminum Oxide Nanoparticles on the Aggregation of Amyloid-Beta in Transgenic Caenorhabditis elegans

    Science.gov (United States)

    Patel, Suhag; Matticks, John; Howell, Carina

    2014-03-01

    The cause of Alzheimer's disease has been linked partially to genetic factors but the predicted environmental components have yet to be determined. In Alzheimer's, accumulation of amyloid-beta protein in the brain forms plaques resulting in neurodegeneration and loss of mental functions. It has been postulated that aluminum influences the aggregation of amyloid-beta. To test this hypothesis, transgenic Caenorhabditis elegans, CL2120, was used as a model organism to observe neurodegeneration in nematodes exposed to aluminum oxide nanoparticles. Behavioral testing, fluorescent staining, and fluorescence microscopy were used to test the effects of aggregation of amyloid-beta in the nervous systems of effected nematodes exposed to aluminum oxide nanoparticles. Energy-dispersive x-ray spectroscopy was used to quantify the total concentration of aluminum oxide that the worms were exposed to during the experiment. Exposure of transgenic and wild type worms to a concentration of 4 mg mL-1 aluminum oxide showed a decrease in the sinusoidal motion, as well as an infirmity of transgenic worms when compared to control worms. These results support the hypothesis that aluminum may play a role in neurodegeneration in C. elegans, and may influence and increase the progression of Alzheimer's disease. This work was supported by National Science Foundation grants DUE-1058829, DMR-0923047 DUE-0806660 and Lock Haven FPDC grants.

  12. Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

    OpenAIRE

    Ryan, N. S.; Lashley, T.; Revesz, T; Dantu, K.; Fox, N.C.; Morris, H R

    2014-01-01

    Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously du...

  13. Effect of Chlorhexidine with Fluoride Mouthrinse on Plaque Accumulation, Plaque pH - A Double Blind Parallel Randomized Clinical Trial

    Science.gov (United States)

    Saha, Sabyasachi; Singh, Sanjay

    2016-01-01

    Introduction Mouthwashes are important means used in chemical control of dental plaque. There is strong evidence suggestive of better effectiveness, when fluoride is added to chlorhexidine mouthwash. Aim To assess the anti-plaque efficacy of Chlorhexidine combined with Fluoride mouthwash and to measure its impact on plaque accumulation and on plaque pH. Materials and Methods Initially 100 subjects were screened. A double blind, parallel randomized clinical trial was conducted on 30 subjects after applying inclusion and exclusion criteria. Other independent variables were matched before randomly allocating them in three groups: Group A-Chlorhexidine as positive control, Group B-Chlorhexidine + Fluoride as test group and Group C- Distilled water as negative control. Oral prophylaxis of participants was done before onset of the study. Plaque pH was assessed before and immediately after rinsing at 0, 5 and 10 minutes interval and after 7 days with digital pH electrode (pHepR pH meter, Hanna Instruments R10285) and accumulation of plaque was recorded by Turesky et al., modification of Quigley Hein Plaque Index (1970). ANOVA test was used for statistical analysis. Results Although there was a statistically significant reduction in mean plaque scores from baseline to seven days in both Groups A and B, Group B showed better anti-plaque efficacy . Almost equal drop in plaque pH was seen for both the groups at 5 and 10 minutes. Conclusion Better anti-plaque efficacy was observed in Group B (Chlorhexidine and Fluoride combination) with minimum variation of plaque pH.

  14. Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?

    Science.gov (United States)

    Moreth, Jens; Mavoungou, Chrystelle; Schindowski, Katharina

    2013-01-01

    Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Aβ) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Aβ-aggregates as the prime toxic agents in AD. However, different Aβ aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Aβ is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Aβ-aggregates than to focus on a single aggregate species for immunization. PMID:23663286

  15. Fibrillar dimer formation of islet amyloid polypeptides

    Energy Technology Data Exchange (ETDEWEB)

    Chiu, Chi-cheng [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States); de Pablo, Juan J. [Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-05-08

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  16. Fibrillar dimer formation of islet amyloid polypeptides

    Science.gov (United States)

    Chiu, Chi-cheng; de Pablo, Juan J.

    2015-09-01

    Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 - 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 - 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

  17. In vivo amyloid imaging in Alzheimer's disease

    International Nuclear Information System (INIS)

    Targeted approaches to therapy for Alzheimer's disease have evolved based on detailed understanding of the genetic, molecular biologic, and neuropathologic basis of the disease. Given the potential for greater treatment efficacy in the earlier stages of the disease, the notion of early diagnosis has become more relevant. Current clinical and imaging diagnostic approaches lack reliability in the preclinical and prodromal phases of the disease. We review emerging studies on imaging of the molecular substrate of the disease, most notably the amyloid peptide, which hope to increase early diagnostic efficacy. We offer a brief overview of the demographics, diagnostic criteria, and current imaging tests, followed by a review of amyloid biology and developments in cerebral amyloid imaging yielded by recent in vitro, in vivo and human studies. (orig.)

  18. [Treatment of familial amyloid polyneuropathy].

    Science.gov (United States)

    Adams, David; Samuel, Didier; Slama, Michel

    2012-09-01

    The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the

  19. Analysis of Amyloid Precursor Protein Function in Drosophila melanogaster.

    Science.gov (United States)

    Cassar, Marlène; Kretzschmar, Doris

    2016-01-01

    The Amyloid precursor protein (APP) has mainly been investigated in connection with its role in Alzheimer's Disease (AD) due to its cleavage resulting in the production of the Aβ peptides that accumulate in the plaques characteristic for this disease. However, APP is an evolutionary conserved protein that is not only found in humans but also in many other species, including Drosophila, suggesting an important physiological function. Besides Aβ, several other fragments are produced by the cleavage of APP; large secreted fragments derived from the N-terminus and a small intracellular C-terminal fragment. Although these fragments have received much less attention than Aβ, a picture about their function is finally emerging. In contrast to mammals, which express three APP family members, Drosophila expresses only one APP protein called APP-like or APPL. Therefore APPL functions can be studied in flies without the complication that other APP family members may have redundant functions. Flies lacking APPL are viable but show defects in neuronal outgrowth in the central and peripheral nervous system (PNS) in addition to synaptic changes. Furthermore, APPL has been connected with axonal transport functions. In the adult nervous system, APPL, and more specifically its secreted fragments, can protect neurons from degeneration. APPL cleavage also prevents glial death. Lastly, APPL was found to be involved in behavioral deficits and in regulating sleep/activity patterns. This review, will describe the role of APPL in neuronal development and maintenance and briefly touch on its emerging function in circadian rhythms while an accompanying review will focus on its role in learning and memory formation. PMID:27507933

  20. On the pathogenesis of IDDM

    DEFF Research Database (Denmark)

    Nerup, J; Mandrup-Poulsen, Thomas; Helqvist, S;

    1994-01-01

    A model of the pathogenesis of insulin-dependent diabetes mellitus, i.e. the initial phase of beta-cell destruction, is proposed: in a cascade-like fashion efficient antigen presentation, unbalanced cytokine, secretion and poor beta-cell defence result in beta-cell destruction by toxic free radic...

  1. Biology and pathogenesis of Acanthamoeba

    OpenAIRE

    Siddiqui Ruqaiyyah; Khan Naveed

    2012-01-01

    Abstract Acanthamoeba is a free-living protist pathogen, capable of causing a blinding keratitis and fatal granulomatous encephalitis. The factors that contribute to Acanthamoeba infections include parasite biology, genetic diversity, environmental spread and host susceptibility, and are highlighted together with potential therapeutic and preventative measures. The use of Acanthamoeba in the study of cellular differentiation mechanisms, motility and phagocytosis, bacterial pathogenesis and ev...

  2. Pathogenesis of postoperative adhesion formation

    NARCIS (Netherlands)

    Hellebrekers, B.W.J.; Kooistra, T.

    2011-01-01

    Background: Current views on the pathogenesis of adhesion formation are based on the "classical concept of adhesion formation", namely that a reduction in peritoneal fibrinolytic activity following peritoneal trauma is of key importance in adhesion development. Methods: A non-systematic literature s

  3. Pathogenesis of motor neuron disease

    Institute of Scientific and Technical Information of China (English)

    Xuefei Wang

    2006-01-01

    OBJECTIVE: To summarize and analyze the factors and theories related to the attack of motor neuron disease, and comprehensively investigate the pathogenesis of motor neuron disease.DATA SOURCES: A search of Pubmed database was undertaken to identify articles about motor neuron disease published in English from January 1994 to June 2006 by using the keywords of "neurodegenerative diseases". Other literatures were collected by retrieving specific journals and articles.STUDY SELECTION: The data were checked primarily, articles related to the pathogenesis of motor neuron disease were involved, and those obviously irrelated to the articles were excluded.DATA EXTRACTION: Totally 54 articles were collected, 30 of them were involved, and the other 24 were excluded.DATA SYNTHESIS: The pathogenesis of motor neuron disease has multiple factors, and the present related theories included free radical oxidation, excitotoxicity, genetic and immune factors, lack of neurotrophic factor,injury of neurofilament, etc. The studies mainly come from transgenic animal models, cell culture in vitro and patients with familial motor neuron disease, but there are still many restrictions and disadvantages.CONCLUSION: It is necessary to try to find whether there is internal association among different mechanisms,comprehensively investigate the pathogenesis of motor neuron diseases, in order to provide reliable evidence for the clinical treatment.

  4. Molecular pathogenesis of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Andersen, Jesper Bøje

    2014-01-01

    Cholangiocarcinoma (CCA) is an orphan cancer of the hepatobiliary tract, the incidence of which has increased in the past decade. The molecular pathogenesis of this treatment-refractory disease is poorly understood. Desmoplasia is a key causal feature of CCA; however, a majority of tumors develop...

  5. Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

    Directory of Open Access Journals (Sweden)

    Hamid Gholami Pourbadie

    Full Text Available The entorhinal cortex (EC is one of the earliest affected brain regions in Alzheimer's disease (AD. EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs, nimodipine and isradipine, were investigated. The amyloid beta (Aβ 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days, almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.

  6. Vascular endothelial growth factor (VEGF and monocyte chemoattractant protein (MCP-1 levels unaltered in symptomatic atherosclerotic carotid plaque patients from North India

    Directory of Open Access Journals (Sweden)

    Dheeraj eKhurana

    2013-04-01

    Full Text Available We aimed to identify the role of vascular endothelial growth factor(VEGF and monocyte chemoattractant protein(MCP-1 as a serum biomarker of symptomatic carotid atherosclerotic plaque in North Indian population. Individuals with symptomatic carotid atherosclerotic plaque have high risk of ischemic stroke. Previous studies from western countries have shown an association between VEGF and MCP-1 levels and the incidence of ischemic stroke. In this study, venous blood from 110 human subjects was collected, 57 blood samples of which were obtained from patients with carotid plaques, 38 neurological controls without carotid plaques and another 15 healthy controls who had no history of serious illness. Serum VEGF and MCP-1 levels were measured using commercially available enzyme-linked immunosorbent assay(ELISA. We also correlated the data clinically and carried out risk factor analysis based on the detailed questionnaire obtained from each patient. For risk factor analysis, a total of 70 symptomatic carotid plaque cases and equal number of age and sex matched healthy controls were analyzed. We found that serum VEGF levels in carotid plaque patients did not show any significant change when compared to either of the controls. Similarly, there was no significant upregulation of monocyte chemoattractant protein-1 in the serum of these patients. The risk factor analysis revealed that hypertension, diabetes, and physical inactivity were the main correlates of carotid atherosclerosis(p<0.05. Prevalence of patients was higher residing in urban areas as compared to rural region. We also found that patients coming from mountaineer region were relatively less vulnerable to cerebral atherosclerosis as compared to the ones residing at plain region. We conclude that the pathogenesis of carotid plaques may progress independent of these inflammatory molecules. In parallel, risk factor analysis indicates hypertension, diabetes and sedentary lifestyle as the most

  7. Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications.

    Science.gov (United States)

    Boulouis, Gregoire; Charidimou, Andreas; Greenberg, Steven M

    2016-06-01

    Sporadic cerebral amyloid angiopathy is a small vessel disorder defined pathologically by progressive amyloid deposition in the walls of cortical and leptomeningeal vessels resulting from disruption of a complex balance between production, circulation, and clearance of amyloid-β peptide (Aβ) in the brain. Cerebral amyloid angiopathy is a major cause of lobar symptomatic intracerebral hemorrhage, transient focal neurologic episodes, and a key contributor to vascular cognitive impairment. The mechanisms and consequences of amyloid-β deposition at the pathological level and its neuroimaging manifestations, clinical consequences, and implications for patient care are addressed in this review. PMID:27214698

  8. Model Hirano bodies protect against tau-independent and tau-dependent cell death initiated by the amyloid precursor protein intracellular domain.

    Directory of Open Access Journals (Sweden)

    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.

  9. Overproduction, purification, crystallization and preliminary X-ray analysis of human Fe65-PTB2 in complex with the amyloid precursor protein intracellular domain

    International Nuclear Information System (INIS)

    Alzheimer’s disease is characterized by proteolytic processing of the amyloid precursor protein (APP), which releases the aggregation-prone amyloid-β (Aβ) peptide and liberates the intracellular domain (AICD) that interacts with various adaptor proteins. The crystallized AICD–Fe65-PTB2 complex is of central importance for APP translocation, nuclear signalling, processing and Aβ generation. Alzheimer’s disease is associated with typical brain deposits (senile plaques) that mainly contain the neurotoxic amyloid β peptide. This peptide results from proteolytic processing of the type I transmembrane protein amyloid precursor protein (APP). During this proteolytic pathway the APP intracellular domain (AICD) is released into the cytosol, where it associates with various adaptor proteins. The interaction of the AICD with the C-terminal phosphotyrosine-binding domain of Fe65 (Fe65-PTB2) regulates APP translocation, signalling and processing. Human AICD and Fe65-PTB2 have been cloned, overproduced and purified in large amounts in Escherichia coli. A complex of Fe65-PTB2 with the C-terminal 32 amino acids of the AICD gave well diffracting hexagonal crystals and data have been collected to 2.1 Å resolution. Initial phases obtained by the molecular-replacement method are of good quality and revealed well defined electron density for the substrate peptide

  10. Amyloid-β-Induced Dysregulation of AMPA Receptor Trafficking

    Directory of Open Access Journals (Sweden)

    Sumasri Guntupalli

    2016-01-01

    Full Text Available Evidence from neuropathological, genetic, animal model, and biochemical studies has indicated that the accumulation of amyloid-beta (Aβ is associated with, and probably induces, profound neuronal changes in brain regions critical for memory and cognition in the development of Alzheimer’s disease (AD. There is considerable evidence that synapses are particularly vulnerable to AD, establishing synaptic dysfunction as one of the earliest events in pathogenesis, prior to neuronal loss. It is clear that excessive Aβ levels can disrupt excitatory synaptic transmission and plasticity, mainly due to dysregulation of the AMPA and NMDA glutamate receptors in the brain. Importantly, AMPA receptors are the principal glutamate receptors that mediate fast excitatory neurotransmission. This is essential for synaptic plasticity, a cellular correlate of learning and memory, which are the cognitive functions that are most disrupted in AD. Here we review recent advances in the field and provide insights into the molecular mechanisms that underlie Aβ-induced dysfunction of AMPA receptor trafficking. This review focuses primarily on NMDA receptor- and metabotropic glutamate receptor-mediated signaling. In particular, we highlight several mechanisms that underlie synaptic long-term depression as common signaling pathways that are hijacked by the neurotoxic effects of Aβ.

  11. Amyloid β levels in human red blood cells.

    Directory of Open Access Journals (Sweden)

    Takehiro Kiko

    Full Text Available UNLABELLED: Amyloid β-peptide (Aβ is hypothesized to play a key role by oxidatively impairing the capacity of red blood cells (RBCs to deliver oxygen to the brain. These processes are implicated in the pathogenesis of Alzheimer's disease (AD. Although plasma Aβ has been investigated thoroughly, the presence and distribution of Aβ in human RBCs are still unclear. In this study, we quantitated Aβ40 and Aβ42 in human RBCs with ELISA assays, and provided evidence that significant amounts of Aβ could be detected in RBCs and that the RBC Aβ levels increased with aging. The RBC Aβ levels increased with aging. On the other hand, providing an antioxidant supplement (astaxanthin, a polar carotenoid to humans was found to decrease RBC Aβ as well as oxidative stress marker levels. These results suggest that plasma Aβ40 and Aβ42 bind to RBCs (possibly with aging, implying a pathogenic role of RBC Aβ. Moreover, the data indicate that RBC Aβ40 and Aβ42 may constitute biomarkers of AD. As a preventive strategy, therapeutic application of astaxanthin as an Aβ-lowering agent in RBCs could be considered as a possible anti-dementia agent. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN42483402.

  12. Mitochondrial Regulatory Pathways in the Pathogenesis of Alzheimer's Disease.

    Science.gov (United States)

    Adiele, Reginald C; Adiele, Chiedukam A

    2016-07-01

    Alzheimer's disease (AD) is an age-associated neurodegenerative brain disorder with progressive cognitive decline that leads to terminal dementia and death. For decades, amyloid-beta (Aβ) and neurofibrillary tangle (NFT) aggregation hypotheses have dominated studies on the pathogenesis and identification of potential therapeutic targets in AD. Little attention has been paid to the mitochondrial molecular/biochemical pathways leading to AD. Mitochondria play a critical role in cell viability and death including neurons and neuroglia, not only because they regulate energy and oxygen metabolism but also because they regulate cell death pathways. Mitochondrial impairment and oxidative stress are implicated in the pathogenesis of AD. Interestingly, current therapeutics provide symptomatic benefits to AD patients resulting in the use of preventive trials on presymptomatic subjects. This review article elucidates the pathophysiology of AD and emphasizes the need to explore the mitochondrial pathways to provide solutions to unanswered questions in the prevention and treatment of AD. PMID:27392851

  13. [Effect of Root Iron Plaque on Norfloxacin Uptake by Rice].

    Science.gov (United States)

    Ma, Wei; Bao, Yan-yu

    2015-06-01

    In anaerobic condition, release of oxygen by roots to rhyzosphere caused the formation of red plaque of iron oxides or hydroxides on the root surface of rice. The effect of iron plaque on norfloxacin uptake was investigated with solution culture in greenhouse, and the results are showed in the following. The content of iron plaque increased with the increase of Fe2+ concentration in medium. After the addition of norfloxacin in nutrient solution, the content of iron plaques on the root surface decreased to different degree, and the reduction of iron plaques was increasing with the increase of norfloxacin mass concentration. Significant relationships were found between the iron plaques and norfloxacin on the root surface, and the correlation coefficients were 0.959 (norfloxacin mass concentration was 10 mg x L(-1)) and 0.987 (norfloxacin mass concentration was 50 mg x L(-1)), respectively, however, the norfloxacin contents in roots and shoots had no significant correlation with the iron plaques. After addition of different mass concentrations of norfloxacin, the quality distribution percentages of norfloxacin on the root surface and in roots and shoots were 87.7%-97.6%, 0.8%-4.8%, 1.5%-7.5%, respectively, the norfloxacin content on the root surface was far greater than those in roots and shoots. It was therefore concluded that iron plaque on roots was a norfloxacin reservoir for rice plant but had no significant effect on the transfer of norfloxacin to roots and shoots of the rice plant. PMID:26387334

  14. Ultrafast laser ablation for targeted atherosclerotic plaque removal

    Science.gov (United States)

    Lanvin, Thomas; Conkey, Donald B.; Descloux, Laurent; Frobert, Aurelien; Valentin, Jeremy; Goy, Jean-Jacques; Cook, Stéphane; Giraud, Marie-Noelle; Psaltis, Demetri

    2015-07-01

    Coronary artery disease, the main cause of heart disease, develops as immune cells and lipids accumulate into plaques within the coronary arterial wall. As a plaque grows, the tissue layer (fibrous cap) separating it from the blood flow becomes thinner and increasingly susceptible to rupturing and causing a potentially lethal thrombosis. The stabilization and/or treatment of atherosclerotic plaque is required to prevent rupturing and remains an unsolved medical problem. Here we show for the first time targeted, subsurface ablation of atherosclerotic plaque using ultrafast laser pulses. Excised atherosclerotic mouse aortas were ablated with ultrafast near-infrared (NIR) laser pulses. The physical damage was characterized with histological sections of the ablated atherosclerotic arteries from six different mice. The ultrafast ablation system was integrated with optical coherence tomography (OCT) imaging for plaque-specific targeting and monitoring of the resulting ablation volume. We find that ultrafast ablation of plaque just below the surface is possible without causing damage to the fibrous cap, which indicates the potential use of ultrafast ablation for subsurface atherosclerotic plaque removal. We further demonstrate ex vivo subsurface ablation of a plaque volume through a catheter device with the high-energy ultrafast pulse delivered via hollow-core photonic crystal fiber.

  15. New low-viscosity overlay medium for viral plaque assays

    Directory of Open Access Journals (Sweden)

    Garten Wolfgang

    2006-08-01

    Full Text Available Abstract Background Plaque assays in cell culture monolayers under solid or semisolid overlay media are commonly used for quantification of viruses and antiviral substances. To overcome the pitfalls of known overlays, we tested suspensions of microcrystalline cellulose Avicel RC/CL™ as overlay media in the plaque and plaque-inhibition assay of influenza viruses. Results Significantly larger plaques were formed under Avicel-containing media, as compared to agar and methylcellulose (MC overlay media. The plaque size increased with decreasing Avicel concentration, but even very diluted Avicel overlays (0.3% ensured formation of localized plaques. Due to their low viscosity, Avicel overlays were easier to use than methylcellulose overlays, especially in the 96-well culture plates. Furthermore, Avicel overlay could be applied without prior removal of the virus inoculum thus facilitating the assay and reducing chances of cross-contamination. Using neuraminidase inhibitor oseltamivir carboxylate, we demonstrated applicability of the Avicel-based plaque reduction assay for testing of antiviral substances. Conclusion Plaque assay under Avicel-containing overlay media is easier, faster and more sensitive than assays under agar- and methylcellulose overlays. The assay can be readily performed in a 96-well plate format and seems particularly suitable for high-throughput virus titrations, serological studies and experiments on viral drug sensitivity. It may also facilitate work with highly pathogenic agents performed under hampered conditions of bio-safety labs.

  16. Directional spatial frequency analysis of lipid distribution in atherosclerotic plaque

    Science.gov (United States)

    Korn, Clyde; Reese, Eric; Shi, Lingyan; Alfano, Robert; Russell, Stewart

    2016-04-01

    Atherosclerosis is characterized by the growth of fibrous plaques due to the retention of cholesterol and lipids within the artery wall, which can lead to vessel occlusion and cardiac events. One way to evaluate arterial disease is to quantify the amount of lipid present in these plaques, since a higher disease burden is characterized by a higher concentration of lipid. Although therapeutic stimulation of reverse cholesterol transport to reduce cholesterol deposits in plaque has not produced significant results, this may be due to current image analysis methods which use averaging techniques to calculate the total amount of lipid in the plaque without regard to spatial distribution, thereby discarding information that may have significance in marking response to therapy. Here we use Directional Fourier Spatial Frequency (DFSF) analysis to generate a characteristic spatial frequency spectrum for atherosclerotic plaques from C57 Black 6 mice both treated and untreated with a cholesterol scavenging nanoparticle. We then use the Cauchy product of these spectra to classify the images with a support vector machine (SVM). Our results indicate that treated plaque can be distinguished from untreated plaque using this method, where no difference is seen using the spatial averaging method. This work has the potential to increase the effectiveness of current in-vivo methods of plaque detection that also use averaging methods, such as laser speckle imaging and Raman spectroscopy.

  17. Bacterial colonization of psoriasis plaques. Is it relevant?

    Directory of Open Access Journals (Sweden)

    Eva Marcus

    2011-08-01

    Full Text Available Bacterial colonization was investigated retrospectively in patients with plaque psoriasis (n=98 inpatient treatments, n=73 patients. At least one pathogen was found in 46% of all cases. Staphylococcus aureus was the most frequent bacterium. Bacterial colonization of psoriasis plaques could be relevant in individual cases.

  18. Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis.

    Science.gov (United States)

    Melzer, Susanne; Ankri, Rinat; Fixler, Dror; Tarnok, Attila

    2015-11-01

    The composition of atherosclerotic (AS) plaques is crucial concerning rupture, thrombosis and clinical events. Two plaque types are distinguished: stable and vulnerable plaques. Vulnerable plaques are rich in inflammatory cells, mostly only M1 macrophages, and are highly susceptible to rupture. These plaques represent a high risk particularly with the standard invasive diagnosis by coronary angiography. So far there are no non-invasive low-risk clinical approaches available to detect and distinguish AS plaque types in vivo. The perspective review introduces a whole work-flow for a novel approach for non-invasive detection and classification of AS plaques using the diffusion reflection method with gold nanoparticle loaded macrophages in combination with flow and image cytometric analysis for quality assurance. Classical biophotonic methods for AS diagnosis are summarized. Phenotyping of monocytes and macrophages are discussed for specific subset labelling by nanomaterials, as well as existing studies and first experimental proofs of concept for the novel approach are shown. In vitro and in vivo detection of NP loaded macrophages (MΦ). Different ways of MΦ labelling include (1) in vitro labelling in suspension (whole blood or buffy coat) or (2) labelling of short-term MΦ cultures with re-injection of MΦ-NP into the animal to detect migration of the cells in the plaques and (3) in vivo injection of NP into the organism. PMID:26110589

  19. Spectral CT of carotid atherosclerotic plaque: comparison with histology

    International Nuclear Information System (INIS)

    To distinguish components of vulnerable atherosclerotic plaque by imaging their energy response using spectral CT and comparing images with histology. After spectroscopic calibration using phantoms of plaque surrogates, excised human carotid atherosclerotic plaques were imaged using MARS CT using a photon-processing detector with a silicon sensor layer and microfocus X-ray tube (50 kVp, 0.5 mA) at 38-μm voxel size. The plaques were imaged, sectioned and re-imaged using four threshold energies: 10, 16, 22 and 28 keV; then sequentially stained with modified Von Kossa, Perl's Prussian blue and Oil-Red O, and photographed. Relative Hounsfield units across the energies were entered into a linear algebraic material decomposition model to identify the unknown plaque components. Lipid, calcium, iron and water-like components of plaque have distinguishable energy responses to X-ray, visible on spectral CT images. CT images of the plaque surface correlated very well with histological photographs. Calcium deposits (>1,000 μm) in plaque are larger than iron deposits (<100 μm), but could not be distinguished from each other within the same voxel using the energy range available. Spectral CT displays energy information in image form at high spatial resolution, enhancing the intrinsic contrast of lipid, calcium and iron within atheroma. (orig.)

  20. MMP-2/MMP-9 plasma level and brain expression in cerebral amyloid angiopathy-associated hemorrhagic stroke.

    Science.gov (United States)

    Hernandez-Guillamon, Mar; Martinez-Saez, Elena; Delgado, Pilar; Domingues-Montanari, Sophie; Boada, Cristina; Penalba, Anna; Boada, Mercè; Pagola, Jorge; Maisterra, Olga; Rodriguez-Luna, David; Molina, Carlos A; Rovira, Alex; Alvarez-Sabin, José; Ortega-Aznar, Arantxa; Montaner, Joan

    2012-03-01

    Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in β-amyloid (Aβ)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aβ-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding. PMID:21707819

  1. Amyloid properties of the leader peptide of variant B cystatin C: implications for Alzheimer and macular degeneration.

    Science.gov (United States)

    Sant'Anna, Ricardo; Navarro, Susanna; Ventura, Salvador; Paraoan, Luminita; Foguel, Debora

    2016-03-01

    Variant B (VB) of cystatin C has a mutation in its signal peptide (A25T), which interferes with its processing leading to reduced secretion and partial retention in the vicinity of the mitochondria. There are genetic evidences of the association of VB with Alzheimer's disease (AD) and age-related macular degeneration (AMD). Here, we investigated aggregation and amyloid propensities of unprocessed VB combining computational and in vitro studies. Aggregation predictors revealed the presence of four aggregation-prone regions, with a strong one at the level of the signal peptide, which indeed formed toxic aggregates and mature amyloid fibrils in solution. In light of these results, we propose for the first time the role of the signal peptide in pathogenesis of AD and AMD. PMID:26865059

  2. Bioenergetics in the pathogenesis, progression and treatment of cardiovascular disorders.

    Science.gov (United States)

    Tanner, H A

    1995-05-01

    The aim of this manuscript is to review perturbations in bioenergetics that are redundant denominators in the diversity of factors mediating the pathogenesis and progression of coronary heart disease (CHD), congestive heart failure (CHF), hypertension and arrhythmias. This paper likewise assesses the pharmacodynamics of widely prescribed drugs that enhance cellular respiration, maintain positive inotropic, chronotropic, dromotropic cardiac effects, sustain myocardial biosynthesis, reverse the morbidity of heart disease, and assure low levels of toxicity commensurate with the agent's biocompatability. Conversely, it is essential to delineate the modality of xenobiotic drugs that inhibit energy transformations, enhance the pathogenesis of CHD, worsen survival in CHF, provoke arrhythmogenic effects, and induce serious side-effects. Documented evidence, derived from biochemical, physiological and pharmacological data sources, consistently links inhibited mitochondrial decarboxylation to aberrations in cholesterol metabolism, biosynthesis, and calcium balance. Underutilized citrates evolved from inhibited decarboxylation are degraded to acetyl CoA. The acetate is the source of steroid synthesis; its carbon atoms form the molecular basis for all endogenous cholesterol. Myocardial anoxia, a consequence of the atheromatous plaque, inhibits ATP production, impairs biosynthesis, induces negative cardiac inotropic and chronotropic effects, and enhances the pathogenesis of CHF. Inhibited decarboxylation is likewise a factor in the mobilization of in situ cardiac Ca2+, resulting in arrhythmias provoked by the cation's deficiency. The restoration of calcium homeostasis decreases peripheral vasotension, reducing hypertension. Parameters drawn from endocrinopathies and the new physiological dimension of microgravity are developed to illustrate the detrimental effect of inhibited bioenergetics on cardiac pathomorphism and cardiovascular dysfunction. In conclusion, anabolic agents

  3. Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

    Science.gov (United States)

    Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

    2014-01-01

    Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial. PMID:25345508

  4. Imaging Modalities to Identity Inflammation in an Atherosclerotic Plaque

    International Nuclear Information System (INIS)

    Atherosclerosis is a chronic, progressive, multifocal arterial wall disease caused by local and systemic inflammation responsible for major cardiovascular complications such as myocardial infarction and stroke. With the recent understanding that vulnerable plaque erosion and rupture, with subsequent thrombosis, rather than luminal stenosis, is the underlying cause of acute ischemic events, there has been a shift of focus to understand the mechanisms that make an atherosclerotic plaque unstable or vulnerable to rupture. The presence of inflammation in the atherosclerotic plaque has been considered as one of the initial events which convert a stable plaque into an unstable and vulnerable plaque. This paper systemically reviews the noninvasive and invasive imaging modalities that are currently available to detect this inflammatory process, at least in the intermediate stages, and discusses the ongoing studies that will help us to better understand and identify it at the molecular level

  5. Are herbal mouthwash efficacious over chlorhexidine on the dental plaque?

    Science.gov (United States)

    Gupta, Devanand; Nayan, Swapna; Tippanawar, Harshad K.; Patil, Gaurav I.; Jain, Ankita; Momin, Rizwan K.; Gupta, Rajendra Kumar

    2015-01-01

    Aim: To compare the effect of herbal extract mouthwash and chlorhexidine mouthwash on the dental plaque level. Materials and Methods: The subjects (60 healthy medical students aged ranges between 20 and 25 years) were randomly divided into two groups, that is, the herbal group and the chlorhexidine gluconate mouthwash group. The data were collected at the baseline and 3 days. The plaque was disclosed using erythrosine disclosing agent and their scores were recorded using the Quigley and Hein plaque index modified by Turesky-Gilmore-Glickman. Statistical analysis was carried out later to compare the effect of all the two groups. Results: Our result showed that the chlorhexidine group shows a greater decrease in plaque score followed by herbal extract, but the result was statistically insignificant. Conclusion: The results indicate that herbal mouthwash may prove to be an effective agent owing to its ability to reduce plaque level, especially in low socioeconomic strata. PMID:26130940

  6. Are herbal mouthwash efficacious over chlorhexidine on the dental plaque?

    Directory of Open Access Journals (Sweden)

    Devanand Gupta

    2015-01-01

    Full Text Available Aim: To compare the effect of herbal extract mouthwash and chlorhexidine mouthwash on the dental plaque level. Materials and Methods: The subjects (60 healthy medical students aged ranges between 20 and 25 years were randomly divided into two groups, that is, the herbal group and the chlorhexidine gluconate mouthwash group. The data were collected at the baseline and 3 days. The plaque was disclosed using erythrosine disclosing agent and their scores were recorded using the Quigley and Hein plaque index modified by Turesky-Gilmore-Glickman. Statistical analysis was carried out later to compare the effect of all the two groups. Results: Our result showed that the chlorhexidine group shows a greater decrease in plaque score followed by herbal extract, but the result was statistically insignificant. Conclusion: The results indicate that herbal mouthwash may prove to be an effective agent owing to its ability to reduce plaque level, especially in low socioeconomic strata.

  7. High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis.

    Science.gov (United States)

    Wang, Yi; Qiu, Juhui; Luo, Shisui; Xie, Xiang; Zheng, Yiming; Zhang, Kang; Ye, Zhiyi; Liu, Wanqian; Gregersen, Hans; Wang, Guixue

    2016-12-01

    Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes. Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts. Shear stress (SS) influences the formation and development of atherosclerosis. The current review focuses on the vulnerable plaques observed in the high shear stress (HSS) regions, which localizes at the proximal region of the plaque intruding into the lumen. The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation. These results greatly challenge the established belief that low shear stress is important for expansive remodelling, which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions. PMID:27482467

  8. Monte Carlo dosimetry of I-125 ophthalmic plaques

    International Nuclear Information System (INIS)

    I-125 seeds, mounted on the surface of gold-alloy plaques (1.0 to 2.0 cm in diameter), are used to treat intraocular malignancies. Currently available dose-computation algorithms ignore the perturbing influence of the plaque, assuming the seeds to be immersed in an infinite, homogeneous medium. The authors used a theoretical but physically and geometrically realistic approach, the Monte Carlo method, to calculate the absorbed dose in water arising from I-125 seeds backed by ophthalmic plaques. Preliminary results indicate that the plaque enhances dose by 2% very close to the seed and reduces dose by 4% to 7% at distances beyond 1 cm. Results are presented for various plaque dimensions, alloy compositions, and I-125 seed types in current clinical use

  9. Effect of curcumin and Cu 2+/Zn 2+ ions on the fibrillar aggregates formed by the amyloid peptide and other peptides at the organic-aqueous interface

    Science.gov (United States)

    Sanghamitra, Nusrat J. M.; Varghese, Neenu; Rao, C. N. R.

    2010-08-01

    Characteristic features of a perilous neuro-degenerative disease such as the Alzhiemer's disease is fibrillar plaque formation by the amyloid (Aβ) peptide. We have modelled the formation and disintegration of fibrils by studying the aggregate structures formed by Aβ structural motif diphenylalanine as well as insulin and bovine serum albumin at the organic-aqueous interface. Even small concentrations of curcumin in the organic medium or Cu 2+ and Zn 2+ ions in the aqueous medium are found to break down the fibrillar structures.

  10. Role of endoplasmic reticulum calcium signaling in the pathogenesis of Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Elena ePopugaeva

    2013-09-01

    Full Text Available Alzheimer disease (AD is a major threat of XXI century that is responsible for the majority of dementia in the elderly. Development of effective AD-preventing therapies are the top priority tasks for neuroscience research. Amyloid hypothesis of AD is a dominant idea in the field, but so far all amyloid-targeting therapies have failed in clinical trials. In addition to amyloid accumulation, there are consistent reports of abnormal calcium signaling in AD neurons. AD neurons exhibit enhanced intracellular calcium (Ca2+ liberation from the endoplasmic reticulum (ER and reduced store-operated Ca2+ entry (SOC. These changes occur primarily as a result of ER Ca2+ overload. We argue that normalization of intracellular Ca2+ homeostasis could be a strategy for development of effective disease-modifying therapies. The current review summarizes recent data about changes in ER Ca2+ signaling in AD. Ca2+ channels that are discussed in the current review include: inositol trisphosphate receptors (InsP3R, ryanodine receptors (RyanR, presenilins as ER Ca2+ leak channels and neuronal SOC channels. We discuss how function of these channels is altered in AD and how important are resulting Ca2+ signaling changes for AD pathogenesis.

  11. Relation between plaque type, plaque thickness, blood shear stress, and plaque stress in coronary arteries assessed by X-ray Angiography and Intravascular Ultrasound

    OpenAIRE

    Balocco, Simone; Gatta, Carlo; Alberti, Marina; Carrillo, Xavier; Rigla, Juan; Radeva, Petia

    2012-01-01

    Purpose: Atheromatic plaque progression is affected, among others phenomena, by biomechanical, biochemical, and physiological factors. In this paper, the authors introduce a novel framework able to provide both morphological (vessel radius, plaque thickness, and type) and biomechanical (wall shear stress and Von Mises stress) indices of coronary arteries. Methods: First, the approach reconstructs the three-dimensional morphology of the vessel from intravascular ultrasound(IVUS) and Angiograph...

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

    Science.gov (United States)

    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. PMID:27591545

  13. Automated coronary CT angiography plaque-lumen segmentation

    Science.gov (United States)

    Cline, Harvey E.; Krishnan, Karthik; Napel, Sandy; Rubin, Geoffrey D.; Turner, Wesley D.; Avila, Ricardo S.

    2009-02-01

    We are investigating the feasibility of a computer-aided detection (CAD) system to assist radiologists in diagnosing coronary artery disease in ECG gated cardiac multi-detector CT scans having calcified plaque. Coronary artery stenosis analysis is challenging if calcified plaque or the iodinated blood pool hides viable lumen. The research described herein provides an improved presentation to the radiologist by removing obscuring calcified plaque and blood pool. The algorithm derives a Gaussian estimate of the point spread function (PSF) of the scanner responsible for plaque blooming by fitting measured CTA image profiles. An initial estimate of the extent of calcified plaque is obtained from the image evidence using a simple threshold. The Gaussian PSF estimate is then convolved with the initial plaque estimate to obtain an estimate of the extent of the blooming artifact and this plaque blooming image is subtracted from the CT image to obtain an image largely free of obscuring plaque. In a separate step, the obscuring blood pool is suppressed using morphological operations and adaptive region growing. After processing by our algorithm, we are able to project the segmented plaque-free lumen to form synthetic angiograms free from obstruction. We can also analyze the coronary arteries with vessel tracking and centerline extraction to produce cross sectional images for measuring lumen stenosis. As an additional aid to radiologists, we also produce plots of calcified plaque and lumen cross-sectional area along selected blood vessels. The method was validated using digital phantoms and actual patient data, including in one case, a validation against the results of a catheter angiogram.

  14. Imaging of amyloid deposition in human brain using positron emission tomography and [{sup 18}F]FACT: comparison with [{sup 11}C]PIB

    Energy Technology Data Exchange (ETDEWEB)

    Ito, Hiroshi [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); National Institute of Radiological Sciences, Biophysics Program, Molecular Imaging Center, Chiba (Japan); Shinotoh, Hitoshi; Shimada, Hitoshi; Miyoshi, Michie; Takano, Harumasa; Takahashi, Hidehiko; Arakawa, Ryosuke; Kodaka, Fumitoshi; Ono, Maiko; Eguchi, Yoko; Higuchi, Makoto; Fukumura, Toshimitsu; Suhara, Tetsuya [National Institute of Radiological Sciences, Molecular Imaging Center, Chiba (Japan); Yanai, Kazuhiko; Okamura, Nobuyuki [Tohoku University School of Medicine, Department of Pharmacology, Sendai (Japan)

    2014-04-15

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The {sup 18}F-labeled amyloid tracer, [{sup 18}F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ {sup 11}C ]Pittsburgh compound B (PIB) and [ {sup 18}F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ {sup 11}C ]PIB and [ {sup 18}F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ {sup 18}F ]FACT studies without partial volume correction, while significant differences were observed in [ {sup 11}C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ {sup 18}F ]FACT studies as well as [ {sup 11}C ]PIB. Relatively lower uptakes of [ {sup 11}C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ {sup 18}F ]FACT. Relatively higher uptake of [ {sup 11}C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ {sup 18}F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ {sup 11}C ]PIB and [ {sup 18}F ]FACT might be due to differences

  15. Imaging of amyloid deposition in human brain using positron emission tomography and [18F]FACT: comparison with [11C]PIB

    International Nuclear Information System (INIS)

    The characteristic neuropathological changes in Alzheimer's disease (AD) are deposition of amyloid senile plaques and neurofibrillary tangles. The 18F-labeled amyloid tracer, [18F]2-[(2-{(E)-2-[2-(dimethylamino)-1,3-thiazol-5-yl]vinyl}-1, 3-benzoxazol-6-yl)oxy ]-3-fluoropropan-1-ol (FACT), one of the benzoxazole derivatives, was recently developed. In the present study, deposition of amyloid senile plaques was measured by positron emission tomography (PET) with both [ 11C ]Pittsburgh compound B (PIB) and [ 18F ]FACT in the same subjects, and the regional uptakes of both radiotracers were directly compared. Two PET scans, one of each with [ 11C ]PIB and [ 18F ]FACT, were performed sequentially on six normal control subjects, two mild cognitive impairment (MCI) patients, and six AD patients. The standardized uptake value ratio of brain regions to the cerebellum was calculated with partial volume correction using magnetic resonance (MR) images to remove the effects of white matter accumulation. No significant differences in the cerebral cortical uptake were observed between normal control subjects and AD patients in [ 18F ]FACT studies without partial volume correction, while significant differences were observed in [ 11C ]PIB. After partial volume correction, the cerebral cortical uptake was significantly larger in AD patients than in normal control subjects for [ 18F ]FACT studies as well as [ 11C ]PIB. Relatively lower uptakes of [ 11C ]PIB in distribution were observed in the medial side of the temporal cortex and in the occipital cortex as compared with [ 18F ]FACT. Relatively higher uptake of [ 11C ]PIB in distribution was observed in the frontal and parietal cortices. Since [ 18F ]FACT might bind more preferentially to dense-cored amyloid deposition, regional differences in cerebral cortical uptake between [ 11C ]PIB and [ 18F ]FACT might be due to differences in regional distribution between diffuse and dense-cored amyloid plaque shown in the autoradiographic

  16. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder

    Science.gov (United States)

    Cai, Zhiyou; Yan, Yong; Wang, Yonglong

    2013-01-01

    Background Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer’s disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. Method An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. Results These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. Conclusion On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions

  17. Serum amyloid P inhibits dermal wound healing

    Science.gov (United States)

    The repair of open wounds depends on granulation tissue formation and contraction, which is primarily mediated by myofibroblasts. A subset of myofibroblasts originates from bone-marrow-derived monocytes which differentiate into fibroblast-like cells called fibrocytes. Serum amyloid P (SAP) inhibits ...

  18. Is amyloid A (AA) amyloidosis always secondary?

    OpenAIRE

    Maury, C P; Törnroth, T; Wegelius, O

    1985-01-01

    The case is reported of a patient with systemic AA amyloidosis associated with non-specific mesenteric lymphadenitis and chronic sideropenia. Renal, small bowel, and rectal biopsies showed amyloid deposits containing AA protein, as defined by potassium permanganate sensitivity and by reactivity with AA antiserum. Reversal of the nephrotic syndrome occurred during steroid-azathioprine therapy.

  19. Impact of obesity on disease severity in patients with plaque type psoriasis

    Directory of Open Access Journals (Sweden)

    Nuriye Kayıran

    2014-12-01

    Full Text Available Background and Design: Psoriasis is a chronic inflammatory systemic disease involving the skin, scalp, nails, and the joints and is characterized by periods of remission and exacerbation. Although the pathogenesis of psoriasis is not fully understood, many genetic and environmental factors are believed to have a role in the development of the disease. Obesity, smoking, family history of psoriasis, repetitive physical traumas and major stress disorders are the factors thought to affect the severity and progress of the disease. In this study, we aimed to investigate the effects of obesity on the clinical severity of psoriasis in patients with chronic plaque psoriasis. Materials and Methods: Three hundred twenty-five outpatients with chronic plaque-type psoriasis were enrolled in the study. Body Mass Index (BMI and Psoriasis Area and Severity Index (PASI values were recorded for each patient. Results: When normal, overweight and obese psoriasis patients were compared, a statistically significant difference was not found in disease severity (p=0.707. There was also no significant correlation between BMI and PASI values (r=0.006, p=0916. Conclusion: Although no effect of obesity on the severity of the disease was shown in our study, further controlled population based studies are needed to investigate the possible role of obesity in triggering and beginning of the disease.

  20. Explosive character of the atheroma plaques ablation

    International Nuclear Information System (INIS)

    At the present time, ischemia (heart disease) is a main cause of the death in the world; a promising method for its treatment is the use of the technology of the laser light of raised power for the ablation of the atherosclerosis plaques. In this paper, the thermodynamic processes will be studied at the beginning and during atheroma ablation using Nd-YAG (10-50 w) and Argon (4-10 w) lasers of a theoretical point of view. The spatial distribution of the temperature during the ablation has been modelated by the method of finite volumes. The manifestation of the raised temperature of the tissue at the threshold of the ablation, which describes the explosive nature of the ablation by laser (popcorn effect), is observed and discussed. The results indicate the quantitative differences in the ablation behavior between the two used lasers, which can have important clinical implications particularly in the reduction of thermal damages to surrounding normal tissue. (author)

  1. Imaging Atherosclerotic Plaque Calcification: Translating Biology.

    Science.gov (United States)

    Bailey, Grant; Meadows, Judith; Morrison, Alan R

    2016-08-01

    Calcification of atherosclerotic lesions was long thought to be an age - related, passive process, but increasingly data has revealed that atherosclerotic calcification is a more active process, involving complex signaling pathways and bone-like genetic programs. Initially, imaging of atherosclerotic calcification was limited to gross assessment of calcium burden, which is associated with total atherosclerotic burden and risk of cardiovascular mortality and of all cause mortality. More recently, sophisticated molecular imaging studies of the various processes involved in calcification have begun to elucidate information about plaque calcium composition and consequent vulnerability to rupture, leading to hard cardiovascular events like myocardial infarction. As such, there has been renewed interest in imaging calcification to advance risk assessment accuracy in an evolving era of precision medicine. Here we summarize recent advances in our understanding of the biologic process of atherosclerotic calcification as well as some of the molecular imaging tools used to assess it. PMID:27339750

  2. I-125 plaque therapy for choroidal melanoma

    International Nuclear Information System (INIS)

    Fifty-eight patients have been treated for a chorodial melanoma using an I-125 plaque with a mean follow-up of 43.7 months (range, 15 - 100 mo). The average apical tumor dose was 8.468 cGy with a dose rate of 71 cGy. Tumors in 52 (89%) patients are controlled locally (two were replaqued). There are 46 (79%) NED; seven have died of distant disease and five of other causes. Complications include cataracts (14), angiopathy (four), vitreous homorrhage (five), and neovascular glaucoma (four). Even though 44 patients had posterior tumors (with 25 patients having lesions < 3.0 mm from the optic nerve), no one had optic nerve atrophy

  3. Hydrogen sulfide production from subgingival plaque samples.

    Science.gov (United States)

    Basic, A; Dahlén, G

    2015-10-01

    Periodontitis is a polymicrobial anaerobe infection. Little is known about the dysbiotic microbiota and the role of bacterial metabolites in the disease process. It is suggested that the production of certain waste products in the proteolytic metabolism may work as markers for disease severity. Hydrogen sulfide (H2S) is a gas produced by degradation of proteins in the subgingival pocket. It is highly toxic and believed to have pro-inflammatory properties. We aimed to study H2S production from subgingival plaque samples in relation to disease severity in subjects with natural development of the disease, using a colorimetric method based on bismuth precipitation. In remote areas of northern Thailand, adults with poor oral hygiene habits and a natural development of periodontal disease were examined for their oral health status. H2S production was measured with the bismuth method and subgingival plaque samples were analyzed for the presence of 20 bacterial species with the checkerboard DNA-DNA hybridization technique. In total, 43 subjects were examined (age 40-60 years, mean PI 95 ± 6.6%). Fifty-six percent had moderate periodontal breakdown (CAL > 3  7 mm) on at least one site. Parvimonas micra, Filifactor alocis, Porphyromonas endodontalis and Fusobacterium nucleatum were frequently detected. H2S production could not be correlated to periodontal disease severity (PPD or CAL at sampled sites) or to a specific bacterial composition. Site 21 had statistically lower production of H2S (p = 0.02) compared to 16 and 46. Betel nut chewers had statistically significant lower H2S production (p = 0.01) than non-chewers. Rapid detection and estimation of subgingival H2S production capacity was easily and reliably tested by the colorimetric bismuth sulfide precipitation method. H2S may be a valuable clinical marker for degradation of proteins in the subgingival pocket. PMID:25280920

  4. Potential role of ustekinumab in the treatment of chronic plaque psoriasis

    Directory of Open Access Journals (Sweden)

    Santo Raffaele Mercuri

    2010-05-01

    Full Text Available Santo Raffaele Mercuri1, Luigi Naldi21Unità di Dermatologia, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Università Vita-Salute, Milano, Italy; 2Centro Studi GISED, Fondazione per la Ricerca Ospedale Maggiore, Unità di Dermatologia, Ospedali Riuniti, Bergamo, ItalyAbstract: Psoriasis is a relatively common, chronic and disabling skin disease, with an immune-related pathogenesis and a genetic background which may be triggered by several environmental factors including smoking and infections. There is no cure but several treatment options are available. The treatment of psoriasis is far from being satisfactory due to impractical modalities of topical treatment and suboptimal safety profile of the systemic treatments available. In the last few years, parallel to an improved understanding of the disease pathogenesis, there has been a boost in research on new agents for the treatment of psoriasis. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL-12 and IL-23, is one such new agent. Psoriasis and its management are briefly reviewed before focusing on the evidence for ustekinumab in the treatment of chronic plaque psoriasis through a systematic search of the main registries of ongoing trials up to December 2009. Ustekinumab proved to be very effective short term in the control of clinical manifestations in psoriasis compared with placebo and with etanercept. Long-term and comparative data are still limited. There is a need for continuing research on the long-term effectiveness and safety of the drug.Keywords: ustekinumab, chronic plaque psoriasis

  5. Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques

    Czech Academy of Sciences Publication Activity Database

    Koistinaho, M.; Ort, Michael; Cimadevilla, Jose Maria; Vondrous, R.; Cordell, B.; Koistinaho, J.; Bureš, Jan; Higgins, L.

    2001-01-01

    Roč. 98, č. 4 (2001), s. 14675-14680. ISSN 0027-8424 R&D Projects: GA ČR GA309/00/1656 Institutional research plan: CEZ:AV0Z5011922 Keywords : spatial memory * transgenic mice * alzheimer Subject RIV: FH - Neurology Impact factor: 10.890, year: 2001

  6. In vivo and in vitro evidence that {sup 99m}Tc-HYNIC-interleukin-2 is able to detect T lymphocytes in vulnerable atherosclerotic plaques of the carotid artery

    Energy Technology Data Exchange (ETDEWEB)

    Glaudemans, Andor W.J.M.; Vries, Erik F.J. de; Koole, Michel; Luurtsema, Gert; Slart, Riemer H.J.A. [University Medical Center Groningen (Netherlands). Dept. of Nuclear Medicine and Molecular Imaging; Bonanno, Elena [Univ. of Rome Tor Vergata (Italy). Dept. of Anatomic Pathology; Galli, Filippo [Sapienza Univ, Rome (Italy). Nuclear Medicine Unit; Zeebregts, Clark J. [University Medical Center Groningen (Netherlands). Surgery (Div. Vascular Surgery); Boersma, Hendrikus H. [University Medical Center Groningen (Netherlands). Dept. of Nuclear Medicine and Molecular Imaging; University Medical Center Groningen (Netherlands). Clinical and Hospital Pharmacy; Taurino, Maurizio [Sapienza Univ., Rome (Italy). Vascular Surgery Unit; Signore, Alberto [University Medical Center Groningen (Netherlands). Dept. of Nuclear Medicine and Molecular Imaging; Sapienza Univ, Rome (Italy). Nuclear Medicine Unit

    2014-09-15

    Recent advances in basic science have established that inflammation plays a pivotal role in the pathogenesis of atherosclerosis. Inflammatory cells are thought to be responsible for the transformation of a stable plaque into a vulnerable one. Lymphocytes constitute at least 20 % of infiltrating cells in these vulnerable plaques. Therefore, the interleukin-2 (IL-2) receptor, being overexpressed on activated T lymphocytes, may represent an attractive biomarker for plaque vulnerability. The aim of this study was to evaluate the specificity of radiolabelled IL-2 [{sup 99m}Tc-hydrazinonicotinamide (HYNIC)-IL-2] for imaging the lymphocytic infiltration in carotid plaques in vivo by planar and single photon emission computed tomography (SPECT)/CT imaging and ex vivo by microSPECT and autoradiography. For the in vivo study, ten symptomatic patients with advanced plaques at ultrasound who were scheduled for carotid endarterectomy underwent {sup 99m}Tc-HYNIC-IL-2 scintigraphy. The images were analysed visually on planar and SPECT images and semi-quantitatively on SPECT images by calculating target to background (T/B) ratios. After endarterectomy, immunomorphological evaluation and immunophenotyping were performed on plaque slices. For the ex vivo studies, four additional patients were included and, after in vitro incubation of removed plaques with {sup 99m}Tc-HYNIC-IL-2, autoradiography was performed and microSPECT images were acquired. Visual analysis defined clear {sup 99m}Tc-HYNIC-IL-2 uptake in seven of the ten symptomatic plaques. SPECT/CT allowed visualization in eight of ten. A significant correlation was found between the number of CD25+ lymphocytes and the total number of CD25+ cells in the plaque and the T/B ratio with adjacent carotid artery as background (Pearson's r = 0.89, p = 0.003 and r = 0.87, p = 0.005, respectively). MicroSPECT imaging showed clear {sup 99m}Tc-HYNIC-IL-2 uptake within the plaque wall and not in the lipidic core. With autoradiography

  7. Current and future treatment of amyloid diseases.

    Science.gov (United States)

    Ankarcrona, M; Winblad, B; Monteiro, C; Fearns, C; Powers, E T; Johansson, J; Westermark, G T; Presto, J; Ericzon, B-G; Kelly, J W

    2016-08-01

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. PMID:27165517

  8. Rotaviruses: from pathogenesis to vaccination

    OpenAIRE

    Greenberg, Harry B.; Estes, Mary K.

    2009-01-01

    Rotaviruses cause life-threatening gastroenteritis in children worldwide; the enormous disease burden has focused efforts to develop vaccines and led to the discovery of novel mechanisms of gastrointestinal virus pathogenesis and host responses to infection. Two live-attenuated vaccines for gastroenteritis (Rotateq and Rotarix) have been licensed in many countries. This review summarizes the latest data on these vaccines, their effectiveness and challenges to global vaccination. Recent insigh...

  9. Multiple mechanisms of iron-induced amyloid beta-peptide accumulation in SHSY5Y cells: protective action of negletein.

    Science.gov (United States)

    Banerjee, Priyanjalee; Sahoo, Arghyadip; Anand, Shruti; Ganguly, Anirban; Righi, Giuliana; Bovicelli, Paolo; Saso, Luciano; Chakrabarti, Sasanka

    2014-12-01

    The increased accumulation of iron in the brain in Alzheimer's disease (AD) is well documented, and excess iron is strongly implicated in the pathogenesis of the disease. The adverse effects of accumulated iron in AD brain may include the oxidative stress, altered amyloid beta-metabolism and the augmented toxicity of metal-bound amyloid beta 42. In this study, we have shown that exogenously added iron in the form of ferric ammonium citrate (FAC) leads to considerable accumulation of amyloid precursor protein (APP) without a corresponding change in the concerned gene expression in cultured SHSY5Y cells during exposure up to 48 h. This phenomenon is also associated with increased β-secretase activity and augmented release of amyloid beta 42 in the medium. Further, the increase in β-secretase activity, in SHSY5Y cells, upon exposure to iron apparently involves reactive oxygen species (ROS) and NF-κB activation. The synthetic flavone negletein (5,6-dihydroxy-7-methoxyflavone), which is a known chelator for iron, can significantly prevent the effects of FAC on APP metabolism in SHSY5Y cells. Further, this compound inhibits the iron-dependent formation of ROS and also blocks the iron-induced oligomerization of amyloid beta 42 in vitro. In concentrations used in this study, negletein alone appears to have only marginal toxic effects on cell viability, but, on the other hand, the drug is capable of ameliorating the iron-induced loss of cell viability considerably. Our results provide the initial evidence of potential therapeutic effects of negletein, which should be explored in suitable animal models of AD. PMID:25249289

  10. Epigenetics and Colorectal Cancer Pathogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bardhan, Kankana; Liu, Kebin, E-mail: Kliu@gru.edu [Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912 (United States)

    2013-06-05

    Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.

  11. Nuclear imaging of amyloid deposits based upon thioflavins

    International Nuclear Information System (INIS)

    Full text: Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo in living mice; and 4) one of these compounds has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies and

  12. Nuclear imaging of amyloid deposits based upon thioflavins

    International Nuclear Information System (INIS)

    Alzheimer's Disease (AD) is a chronic neurodegenerative disorders characterized by the presence of amyloid deposits and neurofibrillar tangles in the brain. Direct assessment of local changes of amyloid deposits in vivo would greatly facilitate the diagnosis and therapeutic treatments of AD. The goal of this study is to develop small-molecule probes that can be used to follow amyloid deposition in vivo in patients with neurodegenerative diseases. Over the past years, we set out to develop a series of small molecules based on thioflavins as radiotracers for use in nuclear imaging modalities such as positron emission tomography and single photon emission computed tomography. The potential of these amyloid-imaging agents for in vivo studies of amyloid deposition has been evaluated based on the following methods: 1) spectrophotometric binding. assays with synthetic amyloid-β (Aβ) fibrils and AD brain homogenates; 2) fluorescent staining of brain tissue sections to evaluate specificity of binding to amyloid deposits; 3) fluorescent microscopy in mouse models to determine the brain permeability and characterize the binding specificity in vivo, and 4) PET studies in human subjects diagnosed with AD and age-matched control subjects. To date, we have identified some lead compounds as molecular probes with specificity towards amyloid deposits. The in vitro and in vivo binding properties of these compounds have been demonstrated in the following ways: 1) they selectively binds to Aβ fibrils; 2) they selectively stains amyloid deposits in AD brain tissue sections; 3) they readily penetrates the blood-brain barrier, selectively detects amyloid deposits in vivo iri living mice; and 4) One of these compounds, termed PIB, has been successfully used in PET studies in human subjects. In conclusion, amyloid-imaging probes have been developed that could be used to monitor amyloid load in vivo. Applications of the probes are under investigation for potential pathophysiology studies

  13. Atherosclerotic Plaque Destabilization in Mice: A Comparative Study.

    Directory of Open Access Journals (Sweden)

    Helene Hartwig

    Full Text Available Atherosclerosis-associated diseases are the main cause of mortality and morbidity in western societies. The progression of atherosclerosis is a dynamic process evolving from early to advanced lesions that may become rupture-prone vulnerable plaques. Acute coronary syndromes are the clinical manifestation of life-threatening thrombotic events associated with high-risk vulnerable plaques. Hyperlipidemic mouse models have been extensively used in studying the mechanisms controlling initiation and progression of atherosclerosis. However, the understanding of mechanisms leading to atherosclerotic plaque destabilization has been hampered by the lack of proper animal models mimicking this process. Although various mouse models generate atherosclerotic plaques with histological features of human advanced lesions, a consensus model to study atherosclerotic plaque destabilization is still lacking. Hence, we studied the degree and features of plaque vulnerability in different mouse models of atherosclerotic plaque destabilization and find that the model based on the placement of a shear stress modifier in combination with hypercholesterolemia represent with high incidence the most human like lesions compared to the other models.

  14. Palladium-103 versus iodine-125 for ophthalmic plaque radiotherapy

    International Nuclear Information System (INIS)

    A dosimetry study compared the use of I-125 vs. Pd-103 radioactive seeds for ophthalmic plaque brachytherapy. Pd-103 seeds in ophthalmic plaques were used to treat 15 patients with intraocular malignant melanoma. Computer-aided simulations were performed to evaluate the intraocular dose distribution of I-125 versus Pd-103 ophthalmic plaques (delivering equivalent apex doses). Seven target points were selected. Starting at the outer scleral surface, four were located along the central axis of the plaque: the 1 mm point (the inner sclera), the 6 mm point, the tumors apex, and the opposite eye wall. They also evaluated the fovea, optic nerve, and the lens because they were considered to be critical structures. These studies demonstrated that the lower energy photons generated by Pd-103 seeds (average 21 KeV) in ophthalmic plaques were more rapidly absorbed in tissue than photons generated by I-125 (average 28 KeV). Therefore, during ophthalmic plaque radiotherapy, Pd-103 photons were found to be more rapidly absorbed within the tumor and less likely to reach most normal ocular structures. On average, the use of Pd-103 decreased the dose to the fovea by 5.7%, to the optic nerve by 8.4%, to the lens by 26%, and to the opposite eye wall by 38.4%. Pd-103 ophthalmic plaque brachytherapy resulted in slightly more irradiation of the tumor and less radiation to most normal ocular structures. 36 refs., 1 fig., 3 tabs

  15. Neurogenesis, Neurodegeneration, Interneuron Vulnerability, and Amyloid-β in the Olfactory Bulb of APP/PS1 Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    De la Rosa-Prieto, Carlos; Saiz-Sanchez, Daniel; Ubeda-Banon, Isabel; Flores-Cuadrado, Alicia; Martinez-Marcos, Alino

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, mostly idiopathic and with palliative treatment. Neuropathologically, it is characterized by intracellular neurofibrillary tangles of tau protein and extracellular plaques of amyloid β peptides. The relationship between AD and neurogenesis is unknown, but two facts are particularly relevant. First, early aggregation sites of both proteinopathies include the hippocampal formation and the olfactory bulb (OB), which have been correlated to memory and olfactory deficits, respectively. These areas are well-recognized integration zones of newly-born neurons in the adult brain. Second, molecules, such as amyloid precursor protein (APP) and presenilin-1 are common to both AD etiology and neurogenic development. Adult neurogenesis in AD models has been studied in the hippocampus, but only occasionally addressed in the OB and results are contradictory. To gain insight on the relationship between adult neurogenesis and AD, this work analyzes neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β involvement in the OB of an AD model. Control and double-transgenic mice carrying the APP and the presenilin-1 genes, which give rise amyloid β plaques have been used. BrdU-treated animals have been studied at 16, 30, 43, and 56 weeks of age. New-born cell survival (BrdU), neuronal loss (using neuronal markers NeuN and PGP9.5), differential interneuron (calbindin-, parvalbumin-, calretinin- and somatostatin-expressing populations) vulnerability, and involvement by amyloid β have been analyzed. Neurogenesis increases with aging in the granule cell layer of control animals from 16 to 43 weeks. No neuronal loss has been observed after quantifying NeuN or PGP9.5. Regarding interneuron population vulnerability: calbindin-expressing neurons remains unchanged; parvalbumin-expressing neurons trend to increase with aging in transgenic animals; calretinin-expressing neurons increase with aging in

  16. Plaque Index in Multi-Bracket Fixed Appliances

    International Nuclear Information System (INIS)

    To compare the plaque index in patients receiving multi-bracket fixed orthodontic treatment for various factors like age, gender, socio-economic status, brushing practices, meal habits, types of brackets, types of ligations, use of mouthwash and duration of treatment. Study Design: Cross-sectional analytical study. Place and Duration of Study: Orthodontics Clinic, The Aga Khan University Hospital, from September to November 2011. Methodology: Socio-demographic and clinical modalities were defined and recorded for 131 patients having multi-bracket fixed appliances. The plaque index of subjects were recorded according to the Silness and Loe plaque index method. Independent sample t-test was used to see difference in plaque index in factors having two variables. One way ANOVA and Post-Hoc Tukey tests were used to see difference in plaque index in factors having three variables. Kappa statistics was used to assess inter examiner reliability. P-value 0.05 was taken to be significant. Results: The sample comprised of 37% males (n = 48) and 63% females (n = 83). The plaque index had statistically significant association with practice of brushing i.e., timing of brushing (p=0.001), method of brushing (p=0.08), type of ligatures (p=0.05) and frequency of visits (p=0.01). Conclusion: The plaque accumulation is significantly decreased in subjects who brush the teeth twice or more than twice a day and those who brush their teeth after breakfast. The use of interdental brush and stainless steel ligatures had significantly low plaque. Subjects presenting with more frequent appointments of short-period had significantly less plaque. (author)

  17. Computer assisted treatment planning for 125I ophthalmic plaque radiotherapy

    International Nuclear Information System (INIS)

    This paper describes a computer program for planning the treatment of ocular tumors with 125I plaques. The program permits the input of the tumor configuration into a model eye and facilitates the viewing of the relative geometry of the tumor and various eye structures in different perspectives. Custom-designed 125I plaques can be localized onto the globe, and dose distributions can be calculated and superimposed on the eye structures in any plane or on the inner eye surface. The program allows efficient evaluation of the plaque design in terms of radiation dose distribution relative to the tumor and critical structures

  18. Multimodality imaging of carotid atherosclerotic plaque: Going beyond stenosis

    Science.gov (United States)

    Hingwala, Divyata; Kesavadas, Chandrasekharan; Sylaja, Padmavathy N; Thomas, Bejoy; Kapilamoorthy, Tirur Raman

    2013-01-01

    Apart from the degree of stenosis, the morphology of carotid atherosclerotic plaques and presence of neovascularization are important factors that may help to evaluate the risk and ‘vulnerability’ of plaques and may also influence the choice of treatment. In this article, we aim to describe the techniques and imaging findings on CTA, high resolution MRI and contrast enhanced ultrasound in the evaluation of carotid atherosclerotic plaques. We also discuss a few representative cases from our institute with the related clinical implications. PMID:23986615

  19. Multimodality imaging of carotid atherosclerotic plaque: Going beyond stenosis

    Directory of Open Access Journals (Sweden)

    Divyata Hingwala

    2013-01-01

    Full Text Available Apart from the degree of stenosis, the morphology of carotid atherosclerotic plaques and presence of neovascularization are important factors that may help to evaluate the risk and ′vulnerability′ of plaques and may also influence the choice of treatment. In this article, we aim to describe the techniques and imaging findings on CTA, high resolution MRI and contrast enhanced ultrasound in the evaluation of carotid atherosclerotic plaques. We also discuss a few representative cases from our institute with the related clinical implications.

  20. Thiocyanate supplementation decreases atherosclerotic plaque in mice expressing human myeloperoxidase

    DEFF Research Database (Denmark)

    Morgan, P E; Laura, R P; Maki, R A;

    2015-01-01

    appreciably altered. Serum MPO levels steadily increased in mice on the high-fat diet, however, comparison of SCN(-)-supplemented versus control mice showed no significant changes in MPO protein, cholesterol, or triglyceride levels; thiol levels were decreased in supplemented mice at one time-point. Plaque...... curve (AUC). Mean serum SCN(-) concentrations were elevated in the supplemented mice (200-320 μM) relative to controls (< 120 μM). Normalized aortic root plaque areas at sacrifice were 26% lower in the SCN(-)-supplemented mice compared with controls (P = 0.0417), but plaque morphology was not...

  1. Atherosclerotic plaque detection by confocal Brillouin and Raman microscopies

    Science.gov (United States)

    Meng, Zhaokai; Basagaoglu, Berkay; Yakovlev, Vladislav V.

    2015-02-01

    Atherosclerosis, the development of intraluminal plaque, is a fundamental pathology of cardiovascular system and remains the leading cause of morbidity and mortality worldwide. Biomechanical in nature, plaque rupture occurs when the mechanical properties of the plaque, related to the morphology and viscoelastic properties, are compromised, resulting in intraluminal thrombosis and reduction of coronary blood flow. In this report, we describe the first simultaneous application of confocal Brillouin and Raman microscopies to ex-vivo aortic wall samples. Such a non-invasive, high specific approach allows revealing a direct relationship between the biochemical and mechanical properties of atherosclerotic tissue.

  2. Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease

    OpenAIRE

    Lian, Hong; Litvinchuk, Alexandra; Chiang, Angie C.-A.; Aithmitti, Nadia; Jankowsky, Joanna L.; Zheng, Hui

    2016-01-01

    Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron–glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamics in vitro and amyloid...

  3. A Microliter-Scale High-throughput Screening System with Quantum-Dot Nanoprobes for Amyloid-β Aggregation Inhibitors

    OpenAIRE

    Yukako Ishigaki; Hiroyuki Tanaka; Hiroaki Akama; Toshiki Ogara; Koji Uwai; Kiyotaka Tokuraku

    2013-01-01

    The aggregation of amyloid β protein (Aβ) is a key step in the pathogenesis of Alzheimer’s disease (AD), and therefore inhibitory substances for Aβ aggregation may have preventive and/or therapeutic potential for AD. Here we report a novel microliter-scale high-throughput screening system for Aβ aggregation inhibitors based on fluorescence microscopy-imaging technology with quantum-dot Nanoprobes. This screening system could be analyzed with a 5-µl sample volume when a 1536-well plate was use...

  4. A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases.

    Science.gov (United States)

    Borza, Liana Rada

    2014-01-01

    Protein aggregates are the defining pathological feature of human neurodegenerative diseases. Studies have revealed that mutant huntingtin, polyglutamine-expanded ataxin-1 and ataxin-3 can cause elevated levels of reactive oxygen species in neuronal cells. It has also been indicated that the normal host prion protein behaves as an antioxidant, while the neurotoxic peptide based on the sequence of the scrapie isoform increases hydrogen peroxide toxicity in neuronal cultures. Additionally, not only can oxidative stress contribute to the aggregation of beta-amyloid and alpha-synuclein, but both beta-amyloid and alpha-synuclein can induce oxidative damage. Furthermore, oxidative stressors have been shown to play a critical role in neurofibrillary pathology leading to tau hyperphosphorylation. In conclusion, the present review supports a cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative disorders. PMID:24741770

  5. Fold modulating function: Bacterial toxins to functional amyloids

    Directory of Open Access Journals (Sweden)

    AdnanKhawajaSyed

    2014-08-01

    Full Text Available Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  6. Atomic View of a Toxic Amyloid Small Oligomer

    Energy Technology Data Exchange (ETDEWEB)

    Laganowsky, Arthur; Liu, Cong; Sawaya, Michael R.; Whitelegge, Julian P.; Park, Jiyong; Zhao, Minglei; Pensalfini, Anna; Soriaga, Angela B.; Landau, Meytal; Teng, Poh K.; Cascio, Duilio; Glabe, Charles; Eisenberg, David (UCI); (UCLA)

    2012-04-30

    Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein {alpha}{beta} crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: {beta}-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the {beta}-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.

  7. MRI plaque imaging reveals high-risk carotid plaques especially in diabetic patients irrespective of the degree of stenosis

    Directory of Open Access Journals (Sweden)

    Holzer K

    2010-11-01

    Full Text Available Abstract Background Plaque imaging based on magnetic resonance imaging (MRI represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII. Type 2 diabetes mellitus (DM 2 represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics. Methods 191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available. Results Eleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%. Concordance between histology and MRI-classification was 91.7% (33/36 and showed a Cohen's kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%. Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81], independent of the degree of stenosis. Conclusion DM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients. See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract

  8. Review of ustekinumab, an interleukin-12 and interleukin-23 inhibitor used for the treatment of plaque psoriasis

    Directory of Open Access Journals (Sweden)

    Nora Koutruba

    2010-03-01

    Full Text Available Nora Koutruba, Jason Emer, Mark LebwohlMount Sinai School of Medicine, New York, USAAbstract: The pathogenesis of psoriasis is unknown, although it is generally accepted that this chronic inflammatory skin disorder is a complex autoimmune condition similar to other T-cell mediated disorders. Psoriasis imposes a heavy burden on the lifestyle of those affected due to the psychological, arthritic, and cutaneous morbidities; thus significant research has focused on the genetic and immunologic features of psoriasis in anticipation of more targeted, efficacious, and safe therapies. Recently, CD4+ T helper (Th 17 cells and interleukins (IL-12 and -23 have been important in the pathogenesis of T-cell mediated disorders such as psoriasis and has influenced the development of medications that specifically target these key immunological players. Ustekinumab is a monoclonal antibody belonging to a newly developed class of biological, anti-cytokine medications that notably targets the p40 subunit of both IL-12 and -23, both naturally occurring proteins that are important in regulating the immune system and are understood to play a role in immune-mediated inflammatory disorders. Ustekinumab’s safety and efficacy has been evaluated for the treatment of moderate-to-severe plaque psoriasis in 3 phase III clinical trials, 2 placebo-controlled (PHOENIX 1 and 2, and 1 comparator-controlled (ACCEPT study which proved advantageous in patients who were treatment-naive, previously failed other immunosuppressive medications including cyclosporine or methotrexate, were unresponsive to phototherapy, or were unable to use or tolerate other therapies. Ustekinumab has also been investigated for other indications such as psoriatic arthritis, Crohn’s disease, and relapsing/remitting multiple sclerosis. We present a concise review evaluating the evidence that supports the use of ustekinumab in the treatment of plaque psoriasis and other conditions.Keywords: ustekinumab

  9. The pathogenesis of hyaline arteriolosclerosis.

    OpenAIRE

    Gamble, C. N.

    1986-01-01

    Although hyaline arteriolosclerosis is very common and has been of interest to pathologists for well over 100 years, its pathogenesis has never been determined. This study demonstrates that iC3b bound via an ester linkage to hydroxyl groups on the repeating disaccharide units of hyaluronic acid is a major component of arteriolar hyaline. The deposition of iC3b within the walls of arterioles appears to be due to slow spontaneous activation of the alternative complement pathway and random bindi...

  10. Biology and pathogenesis of Acanthamoeba

    Directory of Open Access Journals (Sweden)

    Siddiqui Ruqaiyyah

    2012-01-01

    Full Text Available Abstract Acanthamoeba is a free-living protist pathogen, capable of causing a blinding keratitis and fatal granulomatous encephalitis. The factors that contribute to Acanthamoeba infections include parasite biology, genetic diversity, environmental spread and host susceptibility, and are highlighted together with potential therapeutic and preventative measures. The use of Acanthamoeba in the study of cellular differentiation mechanisms, motility and phagocytosis, bacterial pathogenesis and evolutionary processes makes it an attractive model organism. There is a significant emphasis on Acanthamoeba as a Trojan horse of other microbes including viral, bacterial, protists and yeast pathogens.

  11. Molecular pathogenesis of hereditary hemochromatosis.

    Science.gov (United States)

    Liu, Jingqi; Pu, Chunwen; Lang, Lang; Qiao, Liang; Abdullahi, Mohanud Abukar Haji; Jiang, Chunmeng

    2016-08-01

    Hereditary hemochromatosis (HH) is an inherited iron overload disorder characterized by normal iron-driven erythropoiesis and abnormal iron metabolism, leading to excess iron deposited in parenchymal cells of liver, heart, and endocrine glands. Iron hormone, hepcidin, plays a critical role in iron homeostasis through interaction with ferroportin (FPN), a major cellular iron exporter. Hepcidin is encoded by hepcidin antimicrobial peptide (HAMP). Mutations in hepcidin and any genes that regulate the biology of hepcidin, including hemochromatosis genes (HFE), Hemojuvelin (HJV), transferring receptor 2 (TFR2) and FPN, result in hemochromatosis. The identification of hepcidin and its role will provide a better understanding for pathogenesis of HH. PMID:27031690

  12. Pathogenesis of Alcoholic Liver Disease.

    Science.gov (United States)

    Dunn, Winston; Shah, Vijay H

    2016-08-01

    Alcoholic liver disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of alcoholic liver disease can be conceptually divided into (1) ethanol-mediated liver injury, (2) inflammatory immune response to injury, (3) intestinal permeability and microbiome changes. Corticosteroids may improve outcomes, but this is controversial and probably only impacts short-term survival. New pathophysiology-based therapies are under study, including antibiotics, caspase inhibition, interleukin-22, anakinra, FXR agonist and others. These studies provide hope for better future outcomes for this difficult disease. PMID:27373608

  13. 3D Isotropic MR Culprit Plaque Visualization of Carotid Plaque Edema and Hemorrhage with Motion Sensitized Blood Suppression

    DEFF Research Database (Denmark)

    Søvsø Szocska Hansen, Esben; Pedersen, Steen Fjord; Bloch, Lars Ø.;

    2014-01-01

    hemorrhage and plaque edema may represent advanced stages of atherosclerosis[1, 2]. In this study, we present a novel multi-contrast 3D motion sensitized black-blood CMR imaging sequence, which detects both plaque edema and hemorrhage with positive contrast. Subjects and Methods The 3D imaging sequence was...... lumen was 39.74±6.75. Discussion/Conclusion In conclusion, the proposed 3D isotropic multi-contrast CMR technique detects plaque edema and hemorrhage with positive contrast and excellent black-blood contrast, which may facilitate evaluation of carotid atherosclerosis. Ongoing studies will include CMR...

  14. Simulations of nucleation and elongation of amyloid fibrils

    OpenAIRE

    Zhang, Jianing; Muthukumar, M.

    2009-01-01

    We present a coarse-grained model for the growth kinetics of amyloid fibrils from solutions of peptides and address the fundamental mechanism of nucleation and elongation by using a lattice Monte Carlo procedure. We reproduce the three main characteristics of nucleation of amyloid fibrils: (1) existence of lag time, (2) occurrence of a critical concentration, and (3) seeding. We find the nucleation of amyloid fibrils to require a quasi-two-dimensional configuration, where a second layer of β ...

  15. Inhibition of Alzheimer amyloid β aggregation by polyvalent trehalose

    International Nuclear Information System (INIS)

    A glycopolymer carrying trehalose was found to suppress the formation of amyloid fibrils from the amyloid β peptide (1-42) (Aβ), as evaluated by thioflavin T assay and atomic force microscopy. Glycopolymers carrying sugar alcohols also changed the aggregation properties of Aβ, and the inhibitory effect depended on the type of sugar and alkyl side chain. Neutralization activity was confirmed by in vitro assay using HeLa cells. The glycopolymer carrying trehalose strongly inhibited amyloid formation and neutralized cytotoxicity.

  16. Moderate-to-Severe Plaque Psoriasis

    Directory of Open Access Journals (Sweden)

    Rocío Prieto-Pérez

    2015-01-01

    Full Text Available Psoriasis is a chronic skin disease in which genetics play a major role. Although many genome-wide association studies have been performed in psoriasis, knowledge of the age at onset remains limited. Therefore, we analyzed 173 single-nucleotide polymorphisms in genes associated with psoriasis and other autoimmune diseases in patients with moderate-to-severe plaque psoriasis type I (early-onset, <40 years or type II (late-onset, ≥40 years and healthy controls. Moreover, we performed a comparison between patients with type I psoriasis and patients with type II psoriasis. Our comparison of a stratified population with type I psoriasis n=155 and healthy controls N=197 is the first to reveal a relationship between the CLMN, FBXL19, CCL4L, C17orf51, TYK2, IL13, SLC22A4, CDKAL1, and HLA-B/MICA genes. When we compared type I psoriasis with type II psoriasis N=36, we found a significant association between age at onset and the genes PSORS6, TNF-α, FCGR2A, TNFR1, CD226, HLA-C, TNFAIP3, and CCHCR1. Moreover, we replicated the association between rs12191877 (HLA-C and type I psoriasis and between type I and type II psoriasis. Our findings highlight the role of genetics in age of onset of psoriasis.

  17. Assessment of dental plaque by optoelectronic methods

    Science.gov (United States)

    Negrutiu, Meda-Lavinia; Sinescu, Cosmin; Bortun, Cristina Maria; Levai, Mihaela-Codrina; Topala, Florin Ionel; Crǎciunescu, Emanuela Lidia; Cojocariu, Andreea Codruta; Duma, Virgil Florin; Podoleanu, Adrian Gh.

    2016-03-01

    The formation of dental biofilm follows specific mechanisms of initial colonization on the surface, microcolony formation, development of organized three dimensional community structures, and detachment from the surface. The structure of the plaque biofilm might restrict the penetration of antimicrobial agents, while bacteria on a surface grow slowly and display a novel phenotype; the consequence of the latter is a reduced sensitivity to inhibitors. The aim of this study was to evaluate with different optoelectronic methods the morphological characteristics of the dental biofilm. The study was performed on samples from 25 patients aged between 18 and 35 years. The methods used in this study were Spectral Domain Optical Coherence Tomography (SD-OCT) working at 870 nm for in vivo evaluations and Scanning Electron Microscopy (SEM) for validations. For each patient a sample of dental biofilm was obtained directly from the vestibular surface of the teeth's. SD-OCT produced C- and B-scans that were used to generate three dimensional (3D) reconstructions of the sample. The results were compared with SEM evaluations. The biofilm network was dramatically destroyed after the professional dental cleaning. OCT noninvasive methods can act as a valuable tool for the 3D characterization of dental biofilms.

  18. Bacterial interactions in pathogenic subgingival plaque.

    Science.gov (United States)

    Ng, Hong Min; Kin, Lin Xin; Dashper, Stuart G; Slakeski, Nada; Butler, Catherine A; Reynolds, Eric C

    2016-05-01

    Chronic periodontitis has a polymicrobial biofilm aetiology. Polymicrobial biofilms are complex, dynamic microbial communities formed by two or more bacterial species that are important for the persistence and proliferation of participating microbes in the environment. Interspecies adherence, which often involves bacterial surface-associated molecules, and communications are essential in the spatial and temporal development of a polymicrobial biofilm, which in turn is necessary for the overall fitness of a well-organized multispecies biofilm community. In the oral cavity, interactions between key oral bacterial species, including Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, are essential for the progression of chronic periodontitis. In vivo, P. gingivalis and T. denticola are frequently found to co-exist in deep periodontal pockets and have been co-localized to the superficial layers of subgingival plaque as microcolony blooms adjacent to the pocket epithelium, suggesting possible interbacterial interactions that contribute towards disease. The motility and chemotactic ability of T. denticola, although not considered as classic virulence factors, are likely to be important in the synergistic biofilm formation with P. gingivalis. In vitro, P. gingivalis and T. denticola display a symbiotic relationship in nutrient utilization and growth promotion. Together these data suggest there is an intimate relationship between these two species that has evolved to enhance their survival and virulence. PMID:26541672

  19. Intracoronary Imaging in the Detection of Vulnerable Plaques.

    Science.gov (United States)

    Batty, Jonathan A; Subba, Shristy; Luke, Peter; Gigi, Li Wing Chi; Sinclair, Hannah; Kunadian, Vijay

    2016-03-01

    Coronary artery disease is the result of atherosclerotic changes to the coronary arterial wall, comprising endothelial dysfunction, vascular inflammation and deposition of lipid-rich macrophage foam cells. Certain high-risk atherosclerotic plaques are vulnerable to disruption, leading to rupture, thrombosis and the clinical sequelae of acute coronary syndrome. Though recognised as the gold standard for evaluating the presence, distribution and severity of atherosclerotic lesions, invasive coronary angiography is incapable of identifying non-stenotic, vulnerable plaques that are responsible for adverse cardiovascular events. The recognition of such limitations has impelled the development of intracoronary imaging technologies, including intravascular ultrasound, optical coherence tomography and near-infrared spectroscopy, which enable the detailed evaluation of the coronary wall and atherosclerotic plaques in clinical practice. This review discusses the present status of invasive imaging technologies; summarises up-to-date, evidence-based clinical guidelines; and addresses questions that remain unanswered with regard to the future of intracoronary plaque imaging. PMID:26879196

  20. Evidence for xylitol 5-P production in human dental plaque

    International Nuclear Information System (INIS)

    The Turku sugar studies indicated that xylitol may possess a caries-therapeutic effect. More recent data show that xylotol exhibits a bacteriostatic activity on a wide range of bacteria based on uptake and expulsion of xylitol. Intracellular xylitol 5-P appears to be a key substance associated with inhibition of bacterial metabolism by xylitol. This has been shown in studies with pure strains of bacteria, mainly Streptococcus mutans. The aim of the present study was to examine if production of xylitol 5-P occurs in freshly collected dental plaque which is exposed to labeled xylitol. Plaque extracts were analyzed by thin-layer chromatography combined with autoradiography and high performance liquid chromatography. Strong indications were obtained that xylitol 5-P is readily produced by dental plaque. No other significant xylitol metabolites were identified. The bacteriostatic properties of xylitol in plaque are a mechanism which may well account for the caries-therapeutic effect of xylitol. (au)