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  1. Neurine, an acetylcholine autolysis product, elevates secreted amyloid-beta protein precursor and amyloid-beta peptide levels, and lowers neuronal cell viability in culture: a role in Alzheimer's disease?

    Science.gov (United States)

    Tweedie, David; Brossi, Arnold; Chen, DeMoa; Ge, Yuan-Wen; Bailey, Jason; Yu, Qian-Sheng; Kamal, Mohammad A; Sambamurti, Kumar; Lahiri, Debomoy K; Greig, Nigel H

    2006-09-01

    Classical hallmarks of Alzheimer's disease (AD) are a synaptic loss, cholinergic neuron death, and abnormal protein deposition, particularly of toxic amyloid-beta peptide (Abeta) that is derived from amyloid-beta protein precursor (AbetaPP) by the action of beta- and gamma-secretases. The trigger(s) initiating the biochemical cascades that underpin these hallmarks have yet to be fully elucidated. The typical forebrain cholinergic cell demise associated with AD brain results in a loss of presynaptic cholinergic markers and acetylcholine (ACh). Neurine (vinyl-trimethyl-ammonium hydroxide) is a breakdown product of ACh, consequent to autolysis and is an organic poison found in cadavre brain. The time- and concentration-dependent actions of neurine were assessed in human neuroblastoma (NB, SK-N-SH) cells in culture by quantifying cell viability by lactate dehydrogenase (LDH) and MTS assay, and AbetaPP and Abeta levels by Western blot and ELISA. NB cells displayed evidence of toxicity to neurine at > or = 3 mg/ml, as demonstrated by elevated LDH levels in the culture media and a reduced cell viability shown by the MTS assay. Using subtoxic concentrations of neurine, elevations in AbetaPP and Abeta1-40 peptide levels were detected in conditioned media samples.

  2. Amyloid Beta Mediates Memory Formation

    Science.gov (United States)

    Garcia-Osta, Ana; Alberini, Cristina M.

    2009-01-01

    The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid [beta] (1-42) peptide (A[beta][1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimer's disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated,…

  3. The prion protein as a receptor for amyloid-beta

    NARCIS (Netherlands)

    Kessels, Helmut W.; Nguyen, Louis N.; Nabavi, Sadegh; Malinow, Roberto

    2010-01-01

    Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic

  4. Specific Triazine Herbicides Induce Amyloid-beta(42) Production

    NARCIS (Netherlands)

    Portelius, Erik; Durieu, Emilie; Bodin, Marion; Cam, Morgane; Pannee, Josef; Leuxe, Charlotte; Mabondzo, Aloise; Oumata, Nassima; Galons, Herve; Lee, Jung Yeol; Chang, Young-Tae; Stuber, Kathrin; Koch, Philipp; Fontaine, Gaelle; Potier, Marie-Claude; Manousopoulou, Antigoni; Garbis, Spiros D.; Covaci, Adrian; Van Dam, Debby; De Deyn, Peter; Karg, Frank; Flajolet, Marc; Omori, Chiori; Hata, Saori; Suzuki, Toshiharu; Blennow, Kaj; Zetterberg, Henrik; Meijer, Laurent

    2016-01-01

    Proteolytic cleavage of the amyloid-beta protein precursor (A beta PP) ecretases leads to extracellular release of amyloid-beta (A beta) peptides. Increased production of A beta(42) over A beta(40) and aggregation into oligomers and plaques constitute an Alzheimer's disease (AD) hallmark.

  5. Amyloid Beta Peptide Folding in Reverse Micelles.

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    Eskici, Gözde; Axelsen, Paul H

    2017-07-19

    Previously published experimental studies have suggested that when the 40-residue amyloid beta peptide is encapsulated in a reverse micelle, it folds into a structure that may nucleate amyloid fibril formation (Yeung, P. S.-W.; Axelsen, P. H. J. Am. Chem. Soc. 2012, 134, 6061 ). The factors that induce the formation of this structure have now been identified in a multi-microsecond simulation of the same reverse micelle system that was studied experimentally. Key features of the polypeptide-micelle interaction include the anchoring of a hydrophobic residue cluster into gaps in the reverse micelle surface, the formation of a beta turn at the anchor point that brings N- and C-terminal segments of the polypeptide into proximity, high ionic strength that promotes intramolecular hydrogen bond formation, and deformation of the reverse micelle surface to facilitate interactions with the surface along the entire length of the polypeptide. Together, these features cause the simulation-derived vibrational spectrum to red shift in a manner that reproduces the red-shift previously reported experimentally. On the basis of these findings, a new mechanism is proposed whereby membranes nucleate fibril formation and facilitate the in-register alignment of polypeptide strands that is characteristic of amyloid fibrils.

  6. Electrochemistry of Alzheimer disease amyloid beta peptides.

    Science.gov (United States)

    Chiorcea-Paquim, Ana-Maria; Enache, Teodor Adrian; Oliveira-Brett, Ana Maria

    2018-02-13

    Alzheimer's disease (AD) is a widespread form of dementia that is estimated to affect 44.4 million people worldwide. AD pathology is closely related to the accumulation of amyloid beta (Aβ) peptides in fibrils and plagues, the small oligomeric intermediate species formed during the Aβ peptides aggregation presenting the highest neurotoxicity. This review discusses the recent advances on the Aβ peptides electrochemical characterisation. The Aβ peptides oxidation at a glassy carbon electrode occurs in one or two steps, depending on the amino acid sequence, length and content. The first electron transfer reaction corresponds to the tyrosine Tyr10 amino acid residue oxidation, and the second to all three histidine (His6, His13 and His14) and one methionine (Met35) amino acid residues. The Aβ peptides aggregation and amyloid fibril formation is electrochemically detected via the electroactive amino acids oxidation peak currents decrease that occurs in a time dependent manner. The Aβ peptides redox behaviour is correlated with changes in the adsorption morphology from initially random coiled structures, corresponding to the Aβ peptide monomers in random coil or in α-helix conformations, to aggregates and protofibrils and two types of fibrils, corresponding to the Aβ peptides in a β-sheet configuration, observed by atomic force microscopy. Electrochemical studies of Aβ peptides aggregation, mediated by the interaction with metal ions, in particular zinc, copper, and iron, and different methodologies concerning the detection of Aβ peptide biomarkers of AD in biological fluids, using electrochemical biosensors, are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

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    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.

  8. Amyloid Beta Peptide Slows Down Sensory-Induced Hippocampal Oscillations

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    Fernando Peña-Ortega

    2012-01-01

    Full Text Available Alzheimer’s disease (AD progresses with a deterioration of hippocampal function that is likely induced by amyloid beta (Aβ oligomers. Hippocampal function is strongly dependent on theta rhythm, and disruptions in this rhythm have been related to the reduction of cognitive performance in AD. Accordingly, both AD patients and AD-transgenic mice show an increase in theta rhythm at rest but a reduction in cognitive-induced theta rhythm. We have previously found that monomers of the short sequence of Aβ (peptide 25–35 reduce sensory-induced theta oscillations. However, considering on the one hand that different Aβ sequences differentially affect hippocampal oscillations and on the other hand that Aβ oligomers seem to be responsible for the cognitive decline observed in AD, here we aimed to explore the effect of Aβ oligomers on sensory-induced theta rhythm. Our results show that intracisternal injection of Aβ1–42 oligomers, which has no significant effect on spontaneous hippocampal activity, disrupts the induction of theta rhythm upon sensory stimulation. Instead of increasing the power in the theta band, the hippocampus of Aβ-treated animals responds to sensory stimulation (tail pinch with an increase in lower frequencies. These findings demonstrate that Aβ alters induced theta rhythm, providing an in vivo model to test for therapeutic approaches to overcome Aβ-induced hippocampal and cognitive dysfunctions.

  9. The effect of tachykinin neuropeptides on amyloid {beta} aggregation

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    Flashner, Efrat [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Raviv, Uri, E-mail: raviv@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel); Friedler, Assaf, E-mail: assaf@chem.ch.huji.ac.il [The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904 (Israel)

    2011-04-01

    Research highlights: {yields} Mechanistic explanation of how tachykinin neuropeptides reduce A{beta}-induced neurotoxicity. {yields} Biophysical studies suggest that tachykinins do not modulate the distribution of A{beta} oligomeric states, but rather may incorporate into the fibrils. {yields} A possible strategy to inhibit toxicity of amyloid fibrils. -- Abstract: A hallmark of Alzheimer's disease is production of amyloid {beta} peptides resulting from aberrant cleavage of the amyloid precursor protein. Amyloid {beta} assembles into fibrils under physiological conditions, through formation of neurotoxic intermediate oligomers. Tachykinin peptides are known to affect amyloid {beta} neurotoxicity in cells. To understand the mechanism of this effect, we studied how tachykinins affect A{beta}(1-40) aggregation in vitro. Fibrils grown in the presence of tachykinins exhibited reduced thioflavin T (ThT) fluorescence, while their morphology, observed in transmission electron microscopy (TEM), did not alter. Cross linking studies revealed that the distribution of low molecular weight species was not affected by tachykinins. Our results suggest that there may be a specific interaction between tachykinins and A{beta}(1-40) that allows them to co-assemble. This effect may explain the reduction of A{beta}(1-40) neurotoxicity in cells treated with tachykinins.

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

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    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

  11. Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

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    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

    2013-04-15

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  12. Microbiosensor for Alzheimer's disease diagnostics: detection of amyloid beta biomarkers.

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    Prabhulkar, Shradha; Piatyszek, Rudolph; Cirrito, John R; Wu, Ze-Zhi; Li, Chen-Zhong

    2012-07-01

    Alzheimer's disease (AD) affects about 35.6 million people worldwide, and if current trends continue with no medical advancement, one in 85 people will be affected by 2050. Thus, there is an urgent need to develop a cost-effective, easy to use, sensor platform to diagnose and study AD. The measurement of peptide amyloid beta (Aβ) found in CSF has been assessed as an avenue to diagnose and study the disease. The quantification of the ratio of Aβ1-40/42 (or Aβ ratio) has been established as a reliable test to diagnose AD through human clinical trials. Therefore, we have developed a multiplexed, implantable immunosensor to detect amyloid beta (Aβ) isoforms using triple barrel carbon fiber microelectrodes as the sensor platform. Antibodies act as the biorecognition element of the sensor and selectively capture and bind Aβ1-40 and Aβ1-42 to the electrode surface. Electrochemistry was used to measure the intrinsic oxidation signal of Aβ at 0.65 V (vs. Ag/AgCl), originating from a single tyrosine residue found at position 10 in its amino acid sequence. Using the proposed immunosensor Aβ1-40 and Aβ1-42 could be specifically detected in CSF from mice within a detection range of 20-50 nM and 20-140 nM respectively. The immunosensor enables real-time, highly sensitive detection of Aβ and opens up the possibilities for diagnostic ex vivo applications and research-based in vivo studies. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  13. Amyloid Beta Peptides Differentially Affect Hippocampal Theta Rhythms In Vitro

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    Armando I. Gutiérrez-Lerma

    2013-01-01

    Full Text Available Soluble amyloid beta peptide (Aβ is responsible for the early cognitive dysfunction observed in Alzheimer's disease. Both cholinergically and glutamatergically induced hippocampal theta rhythms are related to learning and memory, spatial navigation, and spatial memory. However, these two types of theta rhythms are not identical; they are associated with different behaviors and can be differentially modulated by diverse experimental conditions. Therefore, in this study, we aimed to investigate whether or not application of soluble Aβ alters the two types of theta frequency oscillatory network activity generated in rat hippocampal slices by application of the cholinergic and glutamatergic agonists carbachol or DHPG, respectively. Due to previous evidence that oscillatory activity can be differentially affected by different Aβ peptides, we also compared Aβ25−35 and Aβ1−42 for their effects on theta rhythms in vitro at similar concentrations (0.5 to 1.0 μM. We found that Aβ25−35 reduces, with less potency than Aβ1−42, carbachol-induced population theta oscillatory activity. In contrast, DHPG-induced oscillatory activity was not affected by a high concentration of Aβ25−35 but was reduced by Aβ1−42. Our results support the idea that different amyloid peptides might alter specific cellular mechanisms related to the generation of specific neuronal network activities, instead of exerting a generalized inhibitory effect on neuronal network function.

  14. Ginkgo biloba leaf extract reverses amyloid beta-peptide-induced isoprostane production in rat brain in vitro.

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    Brunetti, Luigi; Orlando, Giustino; Menghini, Luigi; Ferrante, Claudio; Chiavaroli, Annalisa; Vacca, Michele

    2006-11-01

    Isoprostanes are prostaglandin (PG) isomers generated from oxygen radical peroxidation of arachidonic acid, which are reliable markers of membrane oxidative damage. Aging is characterized by an imbalance between the generation of reactive oxygen species and antioxidant detoxification pathways. Ginkgo biloba leaf extract is reputed as a neuroprotective antioxidant agent. We have tested the effects of a Ginkgo biloba extract {containing 24.1 % flavonoids and 181 % terpene lactones [bilobalide (0.542 %), ginkgolide A (0.570 %), ginkgolide B (0.293 %), ginkgolide C (0.263 %), and ginkgolide J (0.138 %)]} on the production of 8-iso-PGF2alpha from rat brain synaptosomes obtained from young (3 months old) or aged (12 and 24 months old) rats, both in the basal state and after oxidative stress induced by either hydrogen peroxide or amyloid beta-peptide. Our findings show that Ginkgo biloba extract pretreatment is able to completely reverse both basal and hydrogen peroxide-stimulated isoprostane production (IC50 of 81.92 microM and 31.89 microM, respectively). Amyloid beta-peptide-induced isoprostane production was also inhibited, both in young and aged rats, to a level even lower than that in unstimulated synaptosomes. This suggests that the oxygen radical scavenging properties of the Ginkgo biloba extract are fully effective in young, as well as in old rats, showing a greater inhibition of isoprostane production in the latter.

  15. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease......-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect...... Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti...

  16. Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors

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    Shokouhi S

    2015-04-01

    correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aβ and wS2 than between the cerebrospinal Aβ and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose.Conclusion: The wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aβ accumulation that are difficult to verify with mean SUVR alone.Keywords: amyloid-beta plaques, positron emission tomography, 11C-Pittsburgh compound B, statistical descriptors, two-point correlation function

  17. PEGylated nanoparticles bind to and alter amyloid-beta peptide conformation

    DEFF Research Database (Denmark)

    Brambilla, Davide; Verpillot, Romain; Le Droumaguet, Benjamin

    2012-01-01

    We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs on the int......We have demonstrated that the polyethylene glycol (PEG) corona of long-circulating polymeric nanoparticles (NPs) favors interaction with the amyloid-beta (Aß(1-42)) peptide both in solution and in serum. The influence of PEGylation of poly(alkyl cyanoacrylate) and poly(lactic acid) NPs...

  18. Inhibition of amyloid-beta-induced cell death in human brain pericytes in vitro.

    NARCIS (Netherlands)

    Rensink, A.A.M.; Verbeek, M.M.; Otte-Holler, I.; Donkelaar, H.J. ten; Waal, R.M.W. de; Kremer, H.P.H.

    2002-01-01

    Amyloid-beta protein (A beta) deposition in the cerebral vascular walls is one of the key features of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) carrying the 'Dutch' mutation (HCHWA-D A beta(1-40)) induces pronounced degeneration of

  19. Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats

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    Granic, Ivica; Nyakas, Csaba; Luiten, Paul G. M.; Eisel, Ulrich L. M.; Halmy, Laszlo G.; Gross, Gerhard; Schoemaker, Hans; Moeller, Achim; Nimmrich, Volker

    2010-01-01

    Amyloid-beta (A beta) is toxic to neurons and such toxicity is - at least in part - mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents

  20. Insulin inhibits amyloid beta-induced cell death in cultured human brain pericytes

    NARCIS (Netherlands)

    Rensink, Annemieke A M; Otte-Höller, Irene; de Boer, Roelie; Bosch, Remko R; ten Donkelaar, Hans J; de Waal, Robert M W; Verbeek, Marcel M; Kremer, Berry

    Amyloid-beta (Abeta) deposition in the cerebral arterial and capillary walls is one of the characteristics of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type. In vitro, Abeta1-40, carrying the "Dutch" mutation (DAbeta1-40), induced reproducible degeneration of

  1. Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-beta Isoforms for Early and Differential Dementia Diagnosis

    NARCIS (Netherlands)

    Struyfs, Hanne; Van Broeck, Bianca; Timmers, Maarten; Fransen, Erik; Sleegers, Kristel; Van Broeckhoven, Christine; De Deyn, Peter P.; Streffer, Johannes R.; Mercken, Marc; Engelborghs, Sebastiaan

    2015-01-01

    Background: Overlapping cerebrospinal fluid biomarkers (CSF) levels between Alzheimer's disease (AD) and non-AD patients decrease differential diagnostic accuracy of the AD core CSF biomarkers. Amyloid-beta (A beta) isoforms might improve the AD versus non-AD differential diagnosis. Objective: To

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

    NARCIS (Netherlands)

    Giacomelli, C.E.; 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

  3. Neuroinflammation and Complexes of 17 beta-Hydroxysteroid Dehydrogenase type 10-Amyloid beta in Alzheimer's Disease

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Řípová, D.; Bartoš, A.; Bocková, Markéta; Hegnerová, Kateřina; Říčný, J.; Čechová, L.; Vrajová, M.; Homola, Jiří

    2013-01-01

    Roč. 10, č. 2 (2013), s. 165-173 ISSN 1567-2050 R&D Projects: GA MZd(CZ) NT11225 Institutional support: RVO:67985882 Keywords : Amyloid beta * mitochondrial enzyme * Alzheimer 's disease Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.796, year: 2013

  4. Aloe arborescens Extract Protects IMR-32 Cells against Alzheimer Amyloid Beta Peptide via Inhibition of Radical Peroxide Production.

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    Clementi, Maria Elisabetta; Tringali, Giuseppe; Triggiani, Doriana; Giardina, Bruno

    2015-11-01

    Aloe arborescens is commonly used as a pharmaceutical ingredient for its effect in burn treatment and ability to increase skin wound healing properties. Besides, it is well known to have beneficial phytotherapeutic, anticancer, and radio-protective properties. In this study, we first provided evidence that A. arborescens extract protects IMR32, a neuroblastoma human cellular line, from toxicity induced by beta amyloid, the peptide responsible for Alzheimer's disease. In particular, pretreatment with A. arborescens maintains an elevated cell viability and exerts a protective effect on mitochondrial functionality, as evidenced by oxygen consumption experiments. The protective mechanism exerted by A. arborescens seems be related to lowering of oxidative potential of the cells, as demonstrated by the ROS measurement compared with the results obtained in the presence of amyloid beta (1-42) peptide alone. Based on these preliminary observations we suggest that use ofA. arborescens extract could be developed as agents for the management of AD.

  5. A Humanin Derivative Reduces Amyloid Beta Accumulation and Ameliorates Memory Deficit in Triple Transgenic Mice

    Science.gov (United States)

    Niikura, Takako; Sidahmed, Elkhansa; Hirata-Fukae, Chiho; Aisen, Paul S.; Matsuoka, Yasuji

    2011-01-01

    Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APPswe, tauP310L, and PS-1M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD. PMID:21264226

  6. A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice.

    Directory of Open Access Journals (Sweden)

    Takako Niikura

    Full Text Available Humanin (HN, a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD-related cytotoxicities, including exposure to amyloid beta (Abeta, in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe, tau(P310L, and PS-1(M146V that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G-HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD.

  7. Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

    DEFF Research Database (Denmark)

    Weiner, H L; Lemere, C A; Maron, R

    2000-01-01

    Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated ......Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease...

  8. S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein.

    Science.gov (United States)

    Li, Xue; Zhao, Wencong; Yang, Hongqi; Zhang, Junhong; Ma, Jianjun

    2013-09-25

    Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults. Al-though effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular ho-meostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen species, and decreasing the mitochondrial membrane potential. S14G-humanin restored these responses. The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cell membrane, and restored the disturbed cellular homeostasis, thereby exerting a neu-roprotective effect on hippocampal neurons.

  9. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease

    OpenAIRE

    Sehlin, Dag; Fang, Xiaotian T.; Cato, Linda; Antoni, Gunnar; Lannfelt, Lars; Syvänen, Stina

    2016-01-01

    Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood-brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid beta (A beta) antibody mAb158 is radiolabelled and conjuga...

  10. Amyloid-beta binds catalase with high affinity and inhibits hydrogen peroxide breakdown.

    OpenAIRE

    Milton, N G

    1999-01-01

    Amyloid-beta (Abeta) specifically bound purified catalase with high affinity and inhibited catalase breakdown of H(2)O(2). The Abeta-induced catalase inhibition involved formation of the inactive catalase Compound II and was reversible. CatalaseAbeta interactions provide rapid functional assays for the cytotoxic domain of Abeta and suggest a mechanism for some of the observed actions of Abeta plus catalase in vitro.

  11. Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

    DEFF Research Database (Denmark)

    Zheng, Lin; Kågedal, Katarina; Dehvari, Nodi

    2009-01-01

    There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to int...... to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal Abeta content (Vector...

  12. S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein

    OpenAIRE

    Li, Xue; Zhao, Wencong; Yang, Hongqi; Zhang, Junhong; Ma, Jianjun

    2013-01-01

    Humanin is a potential therapeutic agent for Alzheimer's disease, and its derivative, S14G-humanin, is 1 000-fold stronger in its neuroprotective effect against Alzheimer's disease-relevant insults. Al-though effective, the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear. Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular ho-meostasis through the cell membrane, increasing intracellular calcium, generating reactive oxygen sp...

  13. Sex-dependent actions of amyloid beta peptides on hippocampal choline carriers of postnatal rats

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Říčný, Jan; Kozmiková, I.; Řípová, D.; Zach, P.; Klaschka, Jan

    2006-01-01

    Roč. 31, č. 3 (2006), s. 351-360 ISSN 0364-3190 R&D Projects: GA ČR(CZ) GA305/03/1547 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z10300504 Keywords : amyloid beta peptide * high affinity choline transport * rat hippocampus Subject RIV: ED - Physiology Impact factor: 2.139, year: 2006

  14. A hydrogel biosensor for high selective and sensitive detection of amyloid-beta oligomers

    Directory of Open Access Journals (Sweden)

    Sun LP

    2018-02-01

    Full Text Available Liping Sun,1 Yong Zhong,1 Jie Gui,1 Xianwu Wang,1 Xiaorong Zhuang,2 Jian Weng1 1Key Laboratory of Biomedical Engineering of Fujian Province, Research Center of Biomedical Engineering of Xiamen, Department of Biomaterials, College of Materials, Xiamen University, 2Department of Neurology, The Affiliated Zhongshan Hospital of Xiamen University, Xiamen, People’s Republic of China Background: Alzheimer’s disease (AD is a neurodegenerative disorder characterized by progressive cognitive and memory impairment. It is the most common neurological disease that causes dementia. Soluble amyloid-beta oligomers (AβO in blood or cerebrospinal fluid (CSF are the pathogenic biomarker correlated with AD. Methods: A simple electrochemical biosensor using graphene oxide/gold nanoparticles (GNPs hydrogel electrode was developed in this study. Thiolated cellular prion protein (PrPC peptide probe was immobilized on GNPs of the hydrogel electrode to construct an AβO biosensor. Electrochemical impedance spectroscopy was utilized for AβO analysis. Results: The specific binding between AβO and PrPC probes on the hydrogel electrode resulted in an increase in the electron-transfer resistance. The biosensor showed high specificity and sensitivity for AβO detection. It could selectively differentiate AβO from amyloid-beta (Aβ monomers or fibrils. Meanwhile, it was highly sensitive to detect as low as 0.1 pM AβO in artificial CSF or blood plasma. The linear range for AβO detection is from 0.1 pM to 10 nM. Conclusion: This biosensor could be used as a cost-effective tool for early diagnosis of AD due to its high electrochemical performance and bionic structure. Keywords: Alzheimer’s disease, amyloid-beta oligomer, graphene, gold nanoparticles, biosensor

  15. Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.

    Science.gov (United States)

    Cook, Jacquelynn J; Wildsmith, Kristin R; Gilberto, David B; Holahan, Marie A; Kinney, Gene G; Mathers, Parker D; Michener, Maria S; Price, Eric A; Shearman, Mark S; Simon, Adam J; Wang, Jennifer X; Wu, Guoxin; Yarasheski, Kevin E; Bateman, Randall J

    2010-05-12

    The accumulation of amyloid beta (Abeta) in Alzheimer's disease is caused by an imbalance of production and clearance, which leads to increased soluble Abeta species and extracellular plaque formation in the brain. Multiple Abeta-lowering therapies are currently in development: an important goal is to characterize the molecular mechanisms of action and effects on physiological processing of Abeta, as well as other amyloid precursor protein (APP) metabolites, in models which approximate human Abeta physiology. To this end, we report the translation of the human in vivo stable-isotope-labeling kinetics (SILK) method to a rhesus monkey cisterna magna ported (CMP) nonhuman primate model, and use the model to test the mechanisms of action of a gamma-secretase inhibitor (GSI). A major concern of inhibiting the enzymes which produce Abeta (beta- and gamma-secretase) is that precursors of Abeta may accumulate and cause a rapid increase in Abeta production when enzyme inhibition discontinues. In this study, the GSI MK-0752 was administered to conscious CMP rhesus monkeys in conjunction with in vivo stable-isotope-labeling, and dose-dependently reduced newly generated CNS Abeta. In contrast to systemic Abeta metabolism, CNS Abeta production was not increased after the GSI was cleared. These results indicate that most of the CNS APP was metabolized to products other than Abeta, including C-terminal truncated forms of Abeta: 1-14, 1-15 and 1-16; this demonstrates an alternative degradation pathway for CNS amyloid precursor protein during gamma-secretase inhibition.

  16. Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab')2 fragment

    OpenAIRE

    Syvänen, Stina; Edén, Desireé; Sehlin, Dag

    2017-01-01

    Antibodies and fragments thereof are, because of high selectivity for their targets, considered as potential therapeutics and biomarkers for several neurological disorders. However, due to their large molecular size, antibodies/fragments do not easily penetrate into the brain. The aim of the present study was to improve the brain distribution via adsorptive-mediated transcytosis of an amyloid-beta (A beta) protofibril selective F(ab')2 fragment (F(ab')2-h158). F(ab')2-h158 was cationized to d...

  17. The proton-pump inhibitor lansoprazole enhances amyloid beta production.

    Science.gov (United States)

    Badiola, Nahuai; Alcalde, Victor; Pujol, Albert; Münter, Lisa-Marie; Multhaup, Gerd; Lleó, Alberto; Coma, Mireia; Soler-López, Montserrat; Aloy, Patrick

    2013-01-01

    A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

  18. Metabolic Characterization of Intact Cells Reveals Intracellular Amyloid Beta but Not Its Precursor Protein to Reduce Mitochondrial Respiration.

    Directory of Open Access Journals (Sweden)

    Patrick M Schaefer

    Full Text Available One hallmark of Alzheimer´s disease are senile plaques consisting of amyloid beta (Aβ, which derives from the processing of the amyloid precursor protein (APP. Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimer´s disease and both Aβ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aβ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aβ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1, increasing APP and Aβ levels or Aβ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aβ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aβ-mediated mitochondrial toxicity. Analyzing Aβ localization revealed that intracellular levels of Aβ and an increased spatial association of APP/Aβ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aβ accumulation in Alzheimer´s disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.

  19. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    C. Cheignon

    2018-04-01

    Full Text Available Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer’s disease (AD, an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS when bound to the amyloid-β (Aβ. The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …. This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level. Keywords: Oxidative stress, Amyloid beta peptide, Metal-ions, Reactive oxygen species, Oxidative damages

  20. Memantine Attenuates Alzheimer's Disease-Like Pathology and Cognitive Impairment.

    Directory of Open Access Journals (Sweden)

    Xiaochuan Wang

    Full Text Available Deficiency of protein phosphatase-2A is a key event in Alzheimer's disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1PP2A, which inhibits the phosphatase activity by interacting with its catalytic subunit protein phosphatase-2Ac, is known to be upregulated in Alzheimer's disease brain. In the present study, we overexpressed I1PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1PP2A in Wistar rats. The I1PP2A rats showed a decrease in brain protein phosphatase-2A activity, abnormal hyperphosphorylation of tau, neurodegeneration, an increase in the level of activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal amyloid-beta and spatial reference memory deficit; littermates treated identically but with vector only, i.e., adeno-associated virus vector-1-enhanced GFP, served as a control. Treatment with memantine, a noncompetitive NMDA receptor antagonist which is an approved drug for treatment of Alzheimer's disease, rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer's disease-like pathology and cognitive impairment in adeno-associated virus vector-1-I1PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer's disease patients.

  1. A bifunctional curcumin analogue for two-photon imaging and inhibiting crosslinking of amyloid beta in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Yuan, Peng; Li, Yuyan; Yaseen, Mohammad A; Grutzendler, Jaime; Moore, Anna; Ran, Chongzhao

    2014-10-09

    In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.

  2. The coding sequence of amyloid-beta precursor protein APP contains a neural-specific promoter element.

    NARCIS (Netherlands)

    Collin, R.W.J.; Martens, G.J.M.

    2006-01-01

    The amyloid-beta precursor protein APP is generally accepted to be involved in the pathology of Alzheimer's disease. Since its physiological role is still unclear, we decided to study the function of APP via stable transgenesis in the amphibian Xenopus laevis. However, the application of constructs

  3. A systematic review of amyloid-beta peptides as putative mediators of the association between affective disorders and Alzheimer's disease

    DEFF Research Database (Denmark)

    Abbasowa, Leda; Heegaard, N. H. H.

    2014-01-01

    was to explore clinically founded evidence for amyloid-beta peptides in cerebrospinal fluid and blood as putative biomarkers for affective disorders. Method: Systematic searches in Embase and PubMed databases yielded 23 eligible, observational studies. Results: Despite inconsistencies that were partly ascribed...

  4. Role of caspase-12 in amyloid beta-peptide-induced toxicity in organotypic hippocampal slices cultured for long periods.

    NARCIS (Netherlands)

    Ishige, K.; Takagi, N.; Imai, T.; Rausch, W.D.; Kosuge, Y.; Kihara, T.; Kusama-Eguchi, K.; Ikeda, H.; Cools, A.R.; Waddington, J.L.; Koshikawa, N.; Ito, Y.

    2007-01-01

    Amyloid beta (Abeta) toxicity has been implicated in cell death in the hippocampus, but its specific mechanisms are poorly understood. In this study, Abeta-induced cell death was investigated in organotypic hippocampal slice cultures (OHCs) that were cultured for various periods in vitro. There were

  5. Effect of four medicinal plants on amyloid-beta induced neurotoxicity in SH-SY5Y Cells

    CSIR Research Space (South Africa)

    Adewusi, EA

    2013-01-01

    Full Text Available Amyloid-beta peptide (Aß) is implicated in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder. This study was designed to determine the effect of four medicinal plants used to treat neurodegenerative diseases on Aß...

  6. The soluble transcobalamin receptor (sCD320) is present in cerebrospinal fluid and correlates to dementia-related biomarkers tau proteins and amyloid-beta

    DEFF Research Database (Denmark)

    Abuyaman, Omar; Nexo, Ebba

    2015-01-01

    BACKGROUND: Cellular uptake of vitamin B12 (B12) demands binding of the vitamin to transcobalamin (TC) and recognition of TC-B12 (holoTC) by the receptor CD320. Recently, we identified a soluble form of CD320 (sCD320) in human plasma. Here we present data on the occurrence of this soluble receptor...... phospho-tau (181P) (p-tau), total tau (t-tau) and amyloid-beta 1-42 (Aβ) (n = 177) employing commercial ELISA kits (Innogenetics Company). Size exclusion chromatography was performed on a Superdex 200 column. RESULTS: The median sCD320 concentration in CSF (14 pmol/L) is around five times lower than...

  7. Poor Memory Performance in Aged Cynomolgus Monkeys with Hippocampal Atrophy, Depletion of Amyloid Beta 1-42 and Accumulation of Tau Proteins in Cerebrospinal Fluid

    DEFF Research Database (Denmark)

    Darusman, Huda S; Pandelaki, Jacub; Mulyadi, Rahmad

    2014-01-01

    , aged cynomolgus monkeys were divided into two groups to compare high-performing (n=6) and low-performing (n=6) subjects. Both groups were tested for biomarkers related to Alzheimer's disease and their brains were scanned using structural magnetic resonance imaging. RESULTS: The subjects with poor DRT......BACKGROUND: Due to their similarities in behavior and disease pathology to humans, non-human primate models are desirable to complement small animals as models for the study of age-related dementia. MATERIALS AND METHODS: Based on their performance on delayed response task (DRT) tests of memory...... performance had evidence of atrophy in the hippocampus and cortical areas, significantly lower cerebrospinal fluid levels of amyloid beta amino acid 1-42 (pmemory...

  8. Bloodstream Amyloid-beta (1-40) Peptide, Cognition, and Outcomes in Heart Failure.

    Science.gov (United States)

    Bayes-Genis, Antoni; Barallat, Jaume; de Antonio, Marta; Domingo, Mar; Zamora, Elisabet; Vila, Joan; Subirana, Isaac; Gastelurrutia, Paloma; Pastor, M Cruz; Januzzi, James L; Lupón, Josep

    2017-11-01

    In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF. Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death. Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification. Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  9. Effect of copper (II) ion against elongation behavior of amyloid {beta} fibrils on liposome membranes

    Energy Technology Data Exchange (ETDEWEB)

    Shimanouchi, T.; Onishi, R.; Kitaura, N.; Umakoshi, H.; Kuboi, R. [Division of Chemical Engineering, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama-cho, Toyonaka, Osaka (Japan)

    2012-01-15

    The fibril growth behavior of amyloid {beta} protein (A{beta}) on cell membranes is relating to the progression of Alzheimer's disease. This growth behavior of A{beta} fibrils is sensitively affected by the metal ions, neurotransmitters, or bioreactive substrate. The inhibitory effect of those materials was quantitatively estimated from the viewpoints of ''crystal growth''. In a bulk aqueous solution, copper (II) ion showed the strong inhibitory effect on the growth of A{beta} fibrils. Meanwhile, the addition of a closed-phospholipid bilayer membrane (liposome) could reduce the above inhibitory effect of copper (II) ion. (copyright 2012 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  10. Amyloid beta-peptide(25-35) changes [Ca2+] in hippocampal neurons

    DEFF Research Database (Denmark)

    Mogensen, Helle Smidt; Beatty, D M; Morris, S J

    1998-01-01

    Insoluble aggregates of the amyloid beta-peptide (A beta) is a major constituent of senile plaques found in brains of Alzheimer disease (AD) patients. The detrimental effects of aggregated A beta is associated with an increased intracellular Ca2+ concentration ([Ca2+]i). We examined the effects...... of A beta(25-35) on [Ca2+]i and intracellular H+ concentration ([H+]i) in single hippocampal neurons by real time fluorescence imaging using the Ca(2+)- and H(+)-specific ratio dyes, indo-1 and SNARF-1. Incubation of these cultures with A beta(25-35) for 3-12 days in vitro increased [Ca2+]i and [H+]i...

  11. Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation.

    Science.gov (United States)

    Lee, Chun-Lin; Kuo, Tzong-Fu; Wang, Jyh-Jye; Pan, Tzu-Ming

    2007-11-01

    Amyloid beta (Abeta) peptide related to the onset of Alzheimer's disease (AD) damaged neurons and further resulted in dementia. Monascus-fermented red mold rice (RMR), a traditional Chinese medicine as well as health food, includes monacolins (with the same function as statins) and multifunctional metabolites. In this study, ethanol extract of RMR (RE) was used to evaluate neuroprotection against Abeta40 neurotoxicity in PC12 cells. Furthermore, the effects of dietary administration of RMR on memory and learning abilities are confirmed in an animal model of AD rats infused with Abeta40 into the cerebral ventricle. During continuous Abeta40 infusion for 28 days, the rats of test groups were administered RMR or lovastatin. Memory and learning abilities were evaluated in the water maze and passive avoidance tasks. After sacrifice, cerebral cortex and hippocampus were collected for the examination of AD risk factors. The in vitro results clearly indicate that RE provides stronger neuroprotection in rescuing cell viability as well as repressing inflammatory response and oxidative stress. RMR administration potently reverses the memory deficit in the memory task. Abeta40 infusion increases acetylcholinesterase activity, reactive oxygen species, and lipid peroxidation and decreases total antioxidant status and superoxide dismutase activity in brain, but these damages were potently reversed by RMR administration, and the protection was more significant than that with lovastatin administration. The protection provided by RMR is able to prevent Abeta fibrils from being formed and deposited in hippocampus and further decrease Abeta40 accumulation, even though Abeta40 solution was infused into brain continuously. (c) 2007 Wiley-Liss, Inc.

  12. Cu K-edge X-ray Absorption Spectroscopy Reveals Differential Copper Coordimation Within Amyloid-beta Oligomers Compared to Amyloid-beta Monomers

    Energy Technology Data Exchange (ETDEWEB)

    J Shearer; P Callan; T Tran; V Szalai

    2011-12-31

    The fatal neurodegenerative disorder Alzheimer's disease (AD) has been linked to the formation of soluble neurotoxic oligomers of amyloid-{beta} (A{beta}) peptides. These peptides have high affinities for copper cations. Despite their potential importance in AD neurodegeneration few studies have focused on probing the Cu{sup 2+/1+} coordination environment within A{beta} oligomers. Herein we present a Cu K-edge X-ray absorption spectroscopic study probing the copper-coordination environment within oligomers of A{beta}(42) (sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA). We find that the Cu{sup 2+} cation is contained within a square planar mixed N/O ligand environment within A{beta}(42) oligomers, which is similar to the copper coordination environment of the monomeric forms of {l_brace}Cu{sup II}A{beta}(40){r_brace} and {l_brace}Cu{sup II}A{beta}(16){r_brace}. Reduction of the Cu{sup 2+} cation within the A{beta}(42) oligomers to Cu{sup 1+} yields a highly dioxygen sensitive copper-species that contains Cu{sup 1+} in a tetrahedral coordination geometry. This can be contrasted with monomers of {l_brace}Cu{sup I}A{beta}(40){r_brace} and {l_brace}Cu{sup I}A{beta}(16){r_brace}, which contain copper in a dioxygen inert linear bis-histidine ligand environment [Shearer and Szalai, J. Am. Chem. Soc., 2008, 130, 17826]. The biological implications of these findings are discussed.

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    Pathological hallmarks indicative of Alzheimer's disease (AD), which are the plaques of amyloid beta1-42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers...... angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject - with Memory-affected and low amyloid level, and aged with higher performance in memory...... and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1-42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human...

  14. Aluminum complexing enhances amyloid beta protein penetration of blood-brain barrier.

    Science.gov (United States)

    Banks, William A; Niehoff, Michael L; Drago, Denise; Zatta, Paolo

    2006-10-20

    A significant co-morbidity of Alzheimer's disease and cerebrovascular impairment suggests that cerebrovascular dysregulation is an important feature of dementia. Amyloid beta protein (Abeta), a relevant risk factor in Alzheimer's disease, has neurotoxic properties and is thought to play a critical role in the cognitive impairments. Previously, we demonstrated that the 42mer of Abeta (Abeta42) complexed with aluminum (Al-Abeta42) is much more cytotoxic than non-complexed Abeta42. The level of Abeta in the brain is a balance between synthesis, degradation, and fluxes across the blood-brain barrier (BBB). In the present paper, we determined whether complexing with aluminum affected the ability of radioactively iodinated Abeta to cross the in vivo BBB. We found that the rates of uptake of Al-Abeta42 and Abeta42 were similar, but that Al-Abeta42 was sequestered by brain endothelial cells much less than Abeta42 and so more readily entered the parenchymal space of the brain. Al-Abeta42 also had a longer half-life in blood and had increased permeation at the striatum and thalamus. Brain-to-blood transport was similar for Al-Abeta42 and Abeta42. In conclusion, complexing with aluminum affects some aspects of blood-to-brain permeability so that Al-Abeta42 would have more ready access to brain cells than Abeta42.

  15. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Directory of Open Access Journals (Sweden)

    Bo Zhang-Haagen

    Full Text Available Small proteins like amyloid beta (Aβ monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP by using SANS and dynamic light scattering (DLS. We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  16. Alzheimer's disease and amyloid beta-peptide deposition in the brain: a matter of 'aging'?

    Science.gov (United States)

    Moro, Maria Luisa; Collins, Matthew J; Cappellini, Enrico

    2010-04-01

    Biomolecules can experience aging processes that limit their long-term functionality in organisms. Typical markers of protein aging are spontaneous chemical modifications, such as AAR (amino acid racemization) and AAI (amino acid isomerization), mainly involving aspartate and asparagine residues. Since these modifications may affect folding and turnover, they reduce protein functionality over time and may be linked to pathological conditions. The present mini-review describes evidence of AAR and AAI involvement in the misfolding and brain accumulation of Abeta (amyloid beta-peptide), a central event in AD (Alzheimer's disease) synaptic dysfunctions. Structural alterations introduced by site-specific modifications linked to protein aging may affect Abeta production, polymerization and clearance, and therefore play a pivotal role in the pathogenesis of sporadic and genetic forms of AD. Early changes associated with molecular aging also have significant long-term consequences for Abeta folding and turnover. New fast, reproducible and accurate methods for the screening of protein aging markers in biological samples may contribute to improve diagnostic and therapeutic approaches in AD.

  17. Pulsed hydrogen-deuterium exchange mass spectrometry probes conformational changes in amyloid beta (Aβ) peptide aggregation.

    Science.gov (United States)

    Zhang, Ying; Rempel, Don L; Zhang, Jun; Sharma, Anuj K; Mirica, Liviu M; Gross, Michael L

    2013-09-03

    Probing the conformational changes of amyloid beta (Aβ) peptide aggregation is challenging owing to the vast heterogeneity of the resulting soluble aggregates. To investigate the formation of these aggregates in solution, we designed an MS-based biophysical approach and applied it to the formation of soluble aggregates of the Aβ42 peptide, the proposed causative agent in Alzheimer's disease. The approach incorporates pulsed hydrogen-deuterium exchange coupled with MS analysis. The combined approach provides evidence for a self-catalyzed aggregation with a lag phase, as observed previously by fluorescence methods. Unlike those approaches, pulsed hydrogen-deuterium exchange does not require modified Aβ42 (e.g., labeling with a fluorophore). Furthermore, the approach reveals that the center region of Aβ42 is first to aggregate, followed by the C and N termini. We also found that the lag phase in the aggregation of soluble species is affected by temperature and Cu(2+) ions. This MS approach has sufficient structural resolution to allow interrogation of Aβ aggregation in physiologically relevant environments. This platform should be generally useful for investigating the aggregation of other amyloid-forming proteins and neurotoxic soluble peptide aggregates.

  18. Structural heterogeneity in familial Alzheimer's disease mutants of amyloid-beta peptides.

    Science.gov (United States)

    Chong, Song-Ho; Yim, Janghyun; Ham, Sihyun

    2013-05-01

    Alzheimer's disease is a neurodegenerative disorder characterized by progressive deposition of amyloid-beta (Aβ) peptides in brain parenchyma and cerebral blood vessels. Several pathogenic familial mutations of Aβ peptides have been identified that exhibit enhanced neurotoxicity and aggregative ability. However, knowledge of the structural characteristics of those Aβ mutants is still limited. Here, we report multiple all-atom molecular dynamics simulations of the wild-type 42-residue Aβ peptide (Aβ42) and its Flemish (A21G), Arctic (E22G), Dutch (E22Q), Italian (E22K), and Iowa (D23N) familial mutants in explicit water. After validating our simulations by comparison with available experimental data, we examined common/different features in the secondary and tertiary structures of the wild-type and five familial mutants of Aβ42. We found that Aβ42 peptides display quite heterogeneous secondary and tertiary structure ensembles. Such structural heterogeneity in the monomeric state would facilitate interconversions between various secondary structures during the formation of a β-sheet-rich amyloid fibril, and may also serve as a structural basis of the amyloid polymorphism.

  19. Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations.

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    Payel Das

    Full Text Available Knowledge of the detailed mechanism by which proteins such as human αB- crystallin and human lysozyme inhibit amyloid beta (Aβ peptide aggregation is crucial for designing treatment for Alzheimer's disease. Thus, unconstrained, atomistic molecular dynamics simulations in explicit solvent have been performed to characterize the Aβ17-42 assembly in presence of the αB-crystallin core domain and of lysozyme. Simulations reveal that both inhibitor proteins compete with inter-peptide interaction by binding to the peptides during the early stage of aggregation, which is consistent with their inhibitory action reported in experiments. However, the Aβ binding dynamics appear different for each inhibitor. The binding between crystallin and the peptide monomer, dominated by electrostatics, is relatively weak and transient due to the heterogeneous amino acid distribution of the inhibitor surface. The crystallin-bound Aβ oligomers are relatively long-lived, as they form more extensive contact surface with the inhibitor protein. In contrast, a high local density of arginines from lysozyme allows strong binding with Aβ peptide monomers, resulting in stable complexes. Our findings not only illustrate, in atomic detail, how the amyloid inhibitory mechanism of human αB-crystallin, a natural chaperone, is different from that of human lysozyme, but also may aid de novo design of amyloid inhibitors.

  20. 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.

  1. Monomeric Amyloid Beta Peptide in Hexafluoroisopropanol Detected by Small Angle Neutron Scattering.

    Science.gov (United States)

    Zhang-Haagen, Bo; Biehl, Ralf; Nagel-Steger, Luitgard; Radulescu, Aurel; Richter, Dieter; Willbold, Dieter

    2016-01-01

    Small proteins like amyloid beta (Aβ) monomers are related to neurodegenerative disorders by aggregation to insoluble fibrils. Small angle neutron scattering (SANS) is a nondestructive method to observe the aggregation process in solution. We show that SANS is able to resolve monomers of small molecular weight like Aβ for aggregation studies. We examine Aβ monomers after prolonged storing in d-hexafluoroisopropanol (dHFIP) by using SANS and dynamic light scattering (DLS). We determined the radius of gyration from SANS as 1.0±0.1 nm for Aβ1-40 and 1.6±0.1 nm for Aβ1-42 in agreement with 3D NMR structures in similar solvents suggesting a solvent surface layer with 5% increased density. After initial dissolution in dHFIP Aβ aggregates sediment with a major component of pure monomers showing a hydrodynamic radius of 1.8±0.3 nm for Aβ1-40 and 3.2±0.4 nm for Aβ1-42 including a surface layer of dHFIP solvent molecules.

  2. In vitro screening on amyloid beta modulation of aqueous extracts from plant seeds

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    Yoshinori Okada

    2016-01-01

    Full Text Available Introduction: Glycation process might contribute to both extensive protein cross-linking and oxidative stress in Alzheimer's disease (AD. The amyloid-like aggregation of glycated bovine serum albumin induces apoptosis in the neuronal cell. Dietary supplementation of antioxidants, vitamins, and polyphenols are beneficial to AD, and consumption of fruits and vegetables reduce the risk of AD. We conducted a screening of 14 aqueous extracts from plant seeds (PSAE for inhibitory activity on amyloid beta (Aβ. Materials and Methods: To examine the effects of PSAE on the Aβ (1–42 concentration, PSAE were analyzed by Aβ (1–42 enzyme-linked immunosorbent assay. Furthermore, we carried out an antiglycation experiment of PSAE and an antiaggregation experiment of PSAE to confirm the modification mechanism of PSAE. PSAE were added to buffer containing D-ribose and albumins. The solutions were incubated at 37 °C for 10 days. After incubation, the products were assayed on a fluorophotometer. Results: PSAE associated differential reduction in the levels of Aβ (1–42 (lettuce; 98.7% ± 2.4%, bitter melon; 95.9% ± 2.6%, and corn; 93.9% ± 2.1%, demonstrating that treatment with lettuce seeds extracts (LSE effectively decreases Aβ (1–42 concentration. Among the 14 PSAE, LSE exhibited the second greatest potential for antiglycation. Inhibition of aggregates was not recognized in LSE. Conclusion: These results suggest that LSE reduces the toxicity of Aβ by modifying Aβ.

  3. A role for 12/15 lipoxygenase in the amyloid beta precursor protein metabolism.

    Science.gov (United States)

    Succol, Francesca; Praticò, Domenico

    2007-10-01

    12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans.

  4. Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

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    Bianca Seifert

    2016-01-01

    Full Text Available The neurotrophin brain derived neurotrophic factor (BDNF is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer’s disease (AD. To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42 treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain.

  5. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2012-02-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  6. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease.

    LENUS (Irish Health Repository)

    Hampel, Harald

    2010-06-01

    Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer\\'s disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid beta (Abeta) production and aggregation. In drug development, it is important to co-develop biomarkers for Abeta-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Abeta isoforms (Abeta40\\/Abeta42), soluble APP isoforms, Abeta oligomers and beta-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Abeta-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.

  7. Natural Amyloid-Beta Oligomers Acutely Impair the Formation of a Contextual Fear Memory in Mice

    Science.gov (United States)

    Kittelberger, Kara A.; Piazza, Fabrizio; Tesco, Giuseppina; Reijmers, Leon G.

    2012-01-01

    Memory loss is one of the hallmark symptoms of Alzheimer's disease (AD). It has been proposed that soluble amyloid-beta (Abeta) oligomers acutely impair neuronal function and thereby memory. We here report that natural Abeta oligomers acutely impair contextual fear memory in mice. A natural Abeta oligomer solution containing Abeta monomers, dimers, trimers, and tetramers was derived from the conditioned medium of 7PA2 cells, a cell line that expresses human amyloid precursor protein containing the Val717Phe familial AD mutation. As a control we used 7PA2 conditioned medium from which Abeta oligomers were removed through immunodepletion. Separate groups of mice were injected with Abeta and control solutions through a cannula into the lateral brain ventricle, and subjected to fear conditioning using two tone-shock pairings. One day after fear conditioning, mice were tested for contextual fear memory and tone fear memory in separate retrieval trials. Three experiments were performed. For experiment 1, mice were injected three times: 1 hour before and 3 hours after fear conditioning, and 1 hour before context retrieval. For experiments 2 and 3, mice were injected a single time at 1 hour and 2 hours before fear conditioning respectively. In all three experiments there was no effect on tone fear memory. Injection of Abeta 1 hour before fear conditioning, but not 2 hours before fear conditioning, impaired the formation of a contextual fear memory. In future studies, the acute effect of natural Abeta oligomers on contextual fear memory can be used to identify potential mechanisms and treatments of AD associated memory loss. PMID:22238679

  8. Amyloid beta inhibits olfactory bulb activity and the ability to smell.

    Directory of Open Access Journals (Sweden)

    Reynaldo Alvarado-Martínez

    Full Text Available Early olfactory dysfunction has been consistently reported in both Alzheimer's disease (AD and in transgenic mice that reproduce some features of this disease. In AD transgenic mice, alteration in olfaction has been associated with increased levels of soluble amyloid beta protein (Aβ as well as with alterations in the oscillatory network activity recorded in the olfactory bulb (OB and in the piriform cortex. However, since AD is a multifactorial disease and transgenic mice suffer a variety of adaptive changes, it is still unknown if soluble Aβ, by itself, is responsible for OB dysfunction both at electrophysiological and behavioral levels. Thus, here we tested whether or not Aβ directly affects OB network activity in vitro in slices obtained from mice and rats and if it affects olfactory ability in these rodents. Our results show that Aβ decreases, in a concentration- and time-dependent manner, the network activity of OB slices at clinically relevant concentrations (low nM and in a reversible manner. Moreover, we found that intrabulbar injection of Aβ decreases the olfactory ability of rodents two weeks after application, an effect that is not related to alterations in motor performance or motivation to seek food and that correlates with the presence of Aβ deposits. Our results indicate that Aβ disrupts, at clinically relevant concentrations, the network activity of the OB in vitro and can trigger a disruption in olfaction. These findings open the possibility of exploring the cellular mechanisms involved in early pathological AD as an approach to reduce or halt its progress.

  9. Tau, Amyloid Beta and Deep Brain Stimulation: Aiming to Restore Cognitive Deficit in Alzheimer's Disease.

    Science.gov (United States)

    Mondragón-Rodríguez, Siddhartha; Perry, George; Pena-Ortega, Fernando; Williams, Sylvain

    2017-01-01

    The last two decades have seen a great advance in the data that supports the two current hypotheses in Alzheimer`s disease field, the amyloid beta hypothesis and the tau hypothesis. Not surprisingly, Aβ and tau proteins are currently the major therapeutic research targets for AD treatment. Unfortunately, nothing but moderate success has emerged from such therapeutic approaches. With this in mind, we will discuss deep brain stimulation as a promising therapeutic strategy that aims to restore brain activity. Lastly, in the scope of cognitive deficit restoration, we will discuss the relevance of the limbic formation as a promising neuroanatomical target for deep brain stimulation. Immunohistochemistry for modified tau (phosphorylated at Ser199-202-Thr205 labelled by the antibody AT8) was performed on paraffin-embedded human brain sections providing a detailed characterization of NFT pathology. Abnormally phosphorylated tau protein is the key common marker in several brain diseases such as Alzheimer's disease, Parkinson`s disease, Pick Disease, Down syndrome and frontotemporal dementia and is capable of affecting synaptic events that are critical for memory formation. With this in mind, therapeutic strategies aiming to restore synaptic events could offer better outcomes. The humble success of current therapeutic strategies along with the lack of basic knowledge of the brain disease mechanisms calls for alternatives that benefit patients in the present moment. One of particular interest is the neurostimulation strategy that is already a well-established treatment for several movement disorders and when compared to current Alzheimer`s therapeutic strategies, deep brain stimulation does not directly interfere with the normal protein function, therefore increasing the probability of success.

  10. Amyloid-beta transporter expression at the blood-CSF barrier is age-dependent

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    Pascale Crissey L

    2011-07-01

    Full Text Available Abstract Background Age is the major risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD. There is an accumulation of amyloid-beta peptides (Aβ in both the AD brain and the normal aging brain. Clearance of Aβ from the brain occurs via active transport at the blood-brain barrier (BBB and blood-cerebrospinal fluid barrier (BCSFB. With increasing age, the expression of the Aβ efflux transporters is decreased and the Aβ influx transporter expression is increased at the BBB, adding to the amyloid burden in the brain. Expression of the Aβ transporters at the choroid plexus (CP epithelium as a function of aging was the subject of this study. Methods This project investigated the changes in expression of the Aβ transporters, the low density lipoprotein receptor-related protein-1 (LRP-1, P-glycoprotein (P-gp, LRP-2 (megalin and the receptor for advanced glycation end-products (RAGE at the BCSFB in Brown-Norway/Fischer rats at ages 3, 6, 9, 12, 20, 30 and 36 months, using real time RT-PCR to measure transporter mRNA expression, and immunohistochemistry (IHC to measure transporter protein in isolated rat CP. Results There was an increase in the transcription of the Aβ efflux transporters, LRP-1 and P-gp, no change in RAGE expression and a decrease in LRP-2, the CP epithelium influx transporter, at the BCSFB with aging. Decreased Aβ42 concentration in the CP, as measured by quantitative IHC, was associated with these Aβ transporter alterations. Conclusions Age-dependent alterations in the CP Aβ transporters are associated with a decrease in Aβ42 accumulation in the CP, and are reciprocal to the changes seen in these transporters at the BBB, suggesting a possible compensatory role for the BCSFB in Aβ clearance in aging.

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

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    Huda Shalahudin Darusman

    2014-11-01

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

  12. Effects of breviscapine on amyloid beta 1-42 induced Alzheimer's disease mice: A HPLC-QTOF-MS based plasma metabonomics study.

    Science.gov (United States)

    Xia, Hongjun; Wu, Lingling; Chu, Mengying; Feng, Huimin; Lu, Chunliang; Wang, Qinghe; He, Minghai; Ge, Xiaoqun

    2017-07-01

    Herba Erigerontis has long been used to cure apoplexy hemiplegia and precordial pain in China. In addition, the bioactivities of its total flavonoids-breviscapine included inhibiting amyloid beta (Aβ) fibril formation, antioxidation and metal chelating, which are beneficial to treat Alzheimer's disease (AD). Hence, A HPLC-QTOF-MS based plasma metabonomics approach was applied to investigate the neuroprotective effects of breviscapine on intracerebroventricular injection of aggregated Aβ 1-42 induced AD mice for the first time in the study. Ten potential biomarkers were screened out by multivariate statistical analysis, eight of which were further identified as indoleacrylic acid, C16 sphinganine, LPE (22:6), sulfolithocholic acid, LPC (16:0), PA (22:1/0:0), taurodeoxycholic acid, and PC (0:0/18:0). According to their metabolic pathways, it was supposed that breviscapine ameliorated the learning and memory deficits of AD mice predominantly by regulating phospholipids metabolism, elevating serotonin level and lowering cholesterols content in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. The Role of Neutrophil Proteins on the Amyloid Beta-RAGE Axis

    Science.gov (United States)

    Stock, Amanda J.; Kasus-Jacobi, Anne; Wren, Jonathan D.; Sjoelund, Virginie H.; Prestwich, Glenn D.

    2016-01-01

    We previously showed an elevated expression of the neutrophil protein, cationic antimicrobial protein of 37kDa (CAP37), in brains of patients with Alzheimer’s disease (AD), suggesting that CAP37 could be involved in AD pathogenesis. The first step in determining how CAP37 might contribute to AD pathogenesis was to identify the receptor through which it induces cell responses. To identify a putative receptor, we performed GAMMA analysis to determine genes that positively correlated with CAP37 in terms of expression. Positive correlations with ligands for the receptor for advanced glycation end products (RAGE) were observed. Additionally, CAP37 expression positively correlated with two other neutrophil proteins, neutrophil elastase and cathepsin G. Enzyme-linked immunosorbent assays (ELISAs) demonstrated an interaction between CAP37, neutrophil elastase, and cathepsin G with RAGE. Amyloid beta 1–42 (Aβ1–42), a known RAGE ligand, accumulates in AD brains and interacts with RAGE, contributing to Aβ1–42 neurotoxicity. We questioned whether the binding of CAP37, neutrophil elastase and/or cathepsin G to RAGE could interfere with Aβ1–42 binding to RAGE. Using ELISAs, we determined that CAP37 and neutrophil elastase inhibited binding of Aβ1–42 to RAGE, and this effect was reversed by protease inhibitors in the case of neutrophil elastase. Since neutrophil elastase and cathepsin G have enzymatic activity, mass spectrometry was performed to determine the proteolytic activity of all three neutrophil proteins on Aβ1–42. All three neutrophil proteins bound to Aβ1–42 with different affinities and cleaved Aβ1–42 with different kinetics and substrate specificities. We posit that these neutrophil proteins could modulate neurotoxicity in AD by cleaving Aβ1–42 and influencing the Aβ1–42 –RAGE interaction. Further studies will be required to determine the biological significance of these effects and their relevance in neurodegenerative diseases such as

  14. Donepezil inhibits the amyloid-beta oligomer-induced microglial activation in vitro and in vivo.

    Science.gov (United States)

    Kim, Hyo Geun; Moon, Minho; Choi, Jin Gyu; Park, Gunhyuk; Kim, Ae-Jung; Hur, Jinyoung; Lee, Kyung-Tae; Oh, Myung Sook

    2014-01-01

    Recent studies on Alzheimer's disease (AD) have focused on soluble oligomeric forms of amyloid-beta (Aβ oligomer, AβO) that are directly associated with AD-related pathologies, such as cognitive decline, neurodegeneration, and neuroinflammation. Donepezil is a well-known anti-dementia agent that increases acetylcholine levels through inhibition of acetylcholinesterase. However, a growing body of experimental and clinical studies indicates that donepezil may also provide neuroprotective and disease-modifying effects in AD. Additionally, donepezil has recently been demonstrated to have anti-inflammatory effects against lipopolysaccharides and tau pathology. However, it remains unknown whether donepezil has anti-inflammatory effects against AβO in cultured microglial cells and the brain in animals. Further, the effects of donepezil against AβO-mediated neuronal death, astrogliosis, and memory impairment have also not yet been investigated. Thus, in the present study, we examined the anti-inflammatory effect of donepezil against AβO and its neuroinflammatory mechanisms. Donepezil significantly attenuated the release of inflammatory mediators (prostaglandin E2, interleukin-1 beta, tumor necrosis factor-α, and nitric oxide) from microglia. Donepezil also decreased AβO-induced up-regulation of inducible nitric oxide synthase and cyclooxygenase-2 protein and phosphorylation of p38 mitogen-activated protein kinase as well as translocation of nuclear factor-kappa B. We next showed that donepezil suppresses activated microglia-mediated toxicity in primary hippocampal cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In intrahippocampal AβO-injected mice, donepezil significantly inhibited microgliosis and astrogliosis. Furthermore, behavioral tests revealed that donepezil (2 mg/kg/day, 5 days, p.o.) significantly ameliorated AβO-induced memory impairment. These results suggest that donepezil directly inhibits microglial activation

  15. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    András, Ibolya E.; Toborek, Michal

    2014-01-01

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  16. The Aggregation Potential of the 1-15-and 1-16-Fragments of the Amyloid beta Peptide and Their Influence on the Aggregation of A beta 40

    NARCIS (Netherlands)

    Shabestari, M.; Plug, T.; Motazacker, M. M.; Meeuwenoord, N. J.; Filippov, D. V.; Meijers, J. C. M.; Huber, M.

    2013-01-01

    The aggregation of amyloid beta (A beta) peptide is important in Alzheimer's disease. Shorter A beta fragments may reduce A beta's cytotoxicity and are used in diagnostics. The aggregation of A beta 16 is controversial; Liu et al. (J. Neurosci. Res. 75:162-171, 2004) and Liao et al. (FEBS Lett.

  17. Two distinct β-sheet structures in Italian-mutant amyloid-beta fibrils : a potential link to different clinical phenotypes

    NARCIS (Netherlands)

    Hubin, Ellen; Deroo, Stéphanie; Schierle, Gabriele Kaminksi; Kaminski, Clemens; Serpell, Louise; Subramaniam, Vinod; van Nuland, Nico; Broersen, Kerensa; Raussens, Vincent; Sarroukh, Rabia

    2015-01-01

    Most Alzheimer's disease (AD) cases are late-onset and characterized by the aggregation and deposition of the amyloid-beta (Aβ) peptide in extracellular plaques in the brain. However, a few rare and hereditary Aβ mutations, such as the Italian Glu22-to-Lys (E22K) mutation, guarantee the development

  18. Chronic exposure of NG108-15 cells to amyloid beta peptide (A beta(1-42)) abolishes calcium influx via N-type calcium channels

    Czech Academy of Sciences Publication Activity Database

    Kašparová, Jana; Lisá, Věra; Tuček, Stanislav; Doležal, Vladimír

    2001-01-01

    Roč. 26, 8-9 (2001), s. 1079-1084 ISSN 0364-3190 R&D Projects: GA MZd NF5183 Institutional research plan: CEZ:AV0Z5011922 Keywords : amyloid beta peptide * Alzheimer's disease * calcium Subject RIV: FH - Neurology Impact factor: 1.638, year: 2001

  19. Amyloid Beta and Tau Proteins as Therapeutic Targets for Alzheimer’s Disease Treatment: Rethinking the Current Strategy

    Directory of Open Access Journals (Sweden)

    Siddhartha Mondragón-Rodríguez

    2012-01-01

    Full Text Available Alzheimer’s disease (AD is defined by the concurrence of accumulation of abnormal aggregates composed of two proteins: Amyloid beta (Aβ and tau, and of cellular changes including neurite degeneration and loss of neurons and cognitive functions. Based on their strong association with disease, genetically and pathologically, it is not surprising that there has been a focus towards developing therapies against the aggregated structures. Unfortunately, current therapies have but mild benefit. With this in mind we will focus on the relationship of synaptic plasticity with Aβ and tau protein and their role as potential targets for the development of therapeutic drugs. Finally, we will provide perspectives in developing a multifactorial strategy for AD treatment.

  20. Decreased rhythmic GABAergic septal activity and memory-associated theta oscillations after hippocampal amyloid-beta pathology in the rat.

    Science.gov (United States)

    Villette, Vincent; Poindessous-Jazat, Frédérique; Simon, Axelle; Léna, Clément; Roullot, Elodie; Bellessort, Brice; Epelbaum, Jacques; Dutar, Patrick; Stéphan, Aline

    2010-08-18

    The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta (symbol) oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid beta (Abeta) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal Abeta injections progressively impaired behavioral performances, the associated hippocampal theta power, and theta frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the theta rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal Abeta treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.

  1. Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Zhang, Can; Tian, Xiaoyu; Ross, Alana W.; Moir, Robert D.; Sun, Hongbin; Tanzi, Rudolph E.; Moore, Anna; Ran, Chongzhao

    2015-01-01

    Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer’s disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17–treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development. PMID:26199414

  2. Triptolide Inhibited Cytotoxicity of Differentiated PC12 Cells Induced by Amyloid-Beta25–35 via the Autophagy Pathway

    Science.gov (United States)

    Xu, Pengjuan; Li, Zhigui; Wang, Hui; Zhang, Xiaochen; Yang, Zhuo

    2015-01-01

    Evidence shows that an abnormal deposition of amyloid beta-peptide25–35 (Aβ25–35) was the primary cause of the pathogenesis of Alzheimer’s disease (AD). And the elimination of Aβ25–35 is considered an important target for the treatment of AD. Triptolide (TP), isolated from Tripterygium wilfordii Hook.f. (TWHF), has been shown to possess a broad spectrum of biological profiles, including neurotrophic and neuroprotective effects. In our study investigating the effect and potential mechanism of triptolide on cytotoxicity of differentiated rat pheochromocytoma cell line (the PC12 cell line is often used as a neuronal developmental model) induced by Amyloid-Beta25–35 (Aβ25–35), we used 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyltetrazolium bromide (MTT) assay, flow cytometry, Western blot, and acridine orange staining to detect whether triptolide could inhibit Aβ25–35–induced cell apoptosis. We focused on the potential role of the autophagy pathway in Aβ25–35-treated differentiated PC12 cells. Our experiments show that cell viability is significantly decreased, and the apoptosis increased in Aβ25–35-treated differentiated PC12 cells. Meanwhile, Aβ25–35 treatment increased the expression of microtubule-associated protein light chain 3 II (LC3 II), which indicates an activation of autophagy. However, triptolide could protect differentiated PC12 cells against Aβ25–35-induced cytotoxicity and attenuate Aβ25–35-induced differentiated PC12 cell apoptosis. Triptolide could also suppress the level of autophagy. In order to assess the effect of autophagy on the protective effects of triptolide in differentiated PC12 cells treated with Aβ25–35, we used 3-Methyladenine (3-MA, an autophagy inhibitor) and rapamycin (an autophagy activator). MTT assay showed that 3-MA elevated cell viability compared with the Aβ25–35-treated group and rapamycin inhibits the protection of triptolide. These results suggest that triptolide will repair the

  3. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract

    Science.gov (United States)

    Brewer, Gregory J.; Torricelli, John R.; Lindsey, Amanda L.; Kunz, Elizabeth Z.; Neuman, A.; Fisher, Derek R.; Joseph, James A.

    2009-01-01

    Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca2+ dysregulation were reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS signaling through MAPK and CREB, pathways known to be activated in response to amyloid-beta. Primary hippocampal neurons were isolated and cultured from embryonic, middle-age or old-age (24 months) rats. Blueberry extract was found to be equally neuroprotective against amyloid-beta neurotoxicity at all ages. Increases in amyloid-beta toxicity with age were associated with age-related increases in immunoreactivity of neurons to pERK and an age-independent increase in pCREB. Treatment with blueberry extract strongly inhibited these increases in parallel with neuroprotection. Simultaneous labeling for ROS and for glutathione with dichlorofluorescein and monocholorobimane showed a mechanism of action of blueberry extract to involve transient ROS generation with an increase in the redox buffer, glutathione. We conclude that the increased age-related susceptibility of old-age neurons to amyloid-beta toxicity may be due to higher levels of activation of pERK and pCREB pathways that can be protected by blueberry extract through inhibition of both these pathways through an ROS stress response. These results suggest that the beneficial effects of blueberry extract may involve transient stress signaling and ROS protection that may translate into improved cognition in aging rats and APP/PS1 mice given blueberry extract. PMID:19954954

  4. Docosahexaenoic acid-induced amelioration on impairment of memory learning in amyloid beta-infused rats relates to the decreases of amyloid beta and cholesterol levels in detergent-insoluble membrane fractions.

    Science.gov (United States)

    Hashimoto, Michio; Hossain, Shahdat; Agdul, Haqu; Shido, Osamu

    2005-12-30

    We investigated the effects of dietary administration of docosahexaenoic acid (DHA; C22:6n-3) on the levels of amyloid beta (A beta) peptide (1-40) and cholesterol in the nonionic detergent Triton 100 x-insoluble membrane fractions (DIFs) of the cerebral cortex and, also, on learning-related memory in an animal model of Alzheimer's disease (AD) rats infused with A beta peptide (1-40) into the cerebral ventricle. The infusion increased the levels of A beta peptide and cholesterol in the DIFs concurrently with a significant increase in reference memory errors (measured by eight-arm radial-maze tasks) compared with those of vehicle rats. Conversely, the dietary administration of DHA to AD-model rats decreased the levels of A beta peptide and cholesterol in the DIFs, with the decrease being more prominent in the DHA-administered rats. Regression analysis revealed a significant positive correlation between A beta peptide and each of cholesterol, palmitic acid and stearic acid, and between the number of reference memory errors and each of cholesterol, palmitic, stearic and oleic acid; moreover, a significant negative correlation was observed between the number of reference memory errors and the molar ratio of DHA to palmitic plus stearic acid. These results suggest that DHA-induced protection of memory deficits in AD-model rats is related to the interactions of cholesterol, palmitic acid or stearic acid with A beta peptides in DIFs where DHA ameliorates these interactions.

  5. Methanolic extract of Piper nigrum fruits improves memory impairment by decreasing brain oxidative stress in amyloid beta(1-42) rat model of Alzheimer's disease.

    Science.gov (United States)

    Hritcu, Lucian; Noumedem, Jaurès A; Cioanca, Oana; Hancianu, Monica; Kuete, Victor; Mihasan, Marius

    2014-04-01

    The present study analyzed the possible memory-enhancing and antioxidant proprieties of the methanolic extract of Piper nigrum L. fruits (50 and 100 mg/kg, orally, for 21 days) in amyloid beta(1-42) rat model of Alzheimer's disease. The memory-enhancing effects of the plant extract were studied by means of in vivo (Y-maze and radial arm-maze tasks) approaches. Also, the antioxidant activity in the hippocampus was assessed using superoxide dismutase-, catalase-, glutathione peroxidase-specific activities and the total content of reduced glutathione, malondialdehyde, and protein carbonyl levels. The amyloid beta(1-42)-treated rats exhibited the following: decrease of spontaneous alternations percentage within Y-maze task and increase of working memory and reference memory errors within radial arm-maze task. Administration of the plant extract significantly improved memory performance and exhibited antioxidant potential. Our results suggest that the plant extract ameliorates amyloid beta(1-42)-induced spatial memory impairment by attenuation of the oxidative stress in the rat hippocampus.

  6. Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer’s Disease

    Science.gov (United States)

    Philippens, Ingrid H.; Ormel, Paul R.; Baarends, Guus; Johansson, Maja; Remarque, Ed J.; Doverskog, Magnus

    2016-01-01

    Background: The immune system is increasingly mentioned as a potential target for Alzheimer’s disease (AD) treatment. Objective: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. Methods: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. Results: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. Conclusion: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD. PMID:27662314

  7. Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease.

    Science.gov (United States)

    Philippens, Ingrid H; Ormel, Paul R; Baarends, Guus; Johansson, Maja; Remarque, Ed J; Doverskog, Magnus

    2017-01-01

    The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment. In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aβ) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aβ fibrils and injected in the other hemisphere without Aβ fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aβ and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aβ only, developed any plaques. This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

  8. Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aβ42 mediated neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Andrew M Steffensmeier

    Full Text Available Alzheimer's disease (AD, OMIM: 104300, a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42 aggregates that trigger neuronal cell death by unknown mechanism(s. We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.

  9. Insulin Promotes Survival of Amyloid-Beta Oligomers Neuroblastoma Damaged Cells via Caspase 9 Inhibition and Hsp70 Upregulation

    Directory of Open Access Journals (Sweden)

    M. Di Carlo

    2010-01-01

    Full Text Available Alzheimer's disease (AD and type 2 diabetes are connected in a way that is still not completely understood, but insulin resistance has been implicated as a risk factor for developing AD. Here we show an evidence that insulin is capable of reducing cytotoxicity induced by Amyloid-beta peptides (A-beta in its oligomeric form in a dose-dependent manner. By TUNEL and biochemical assays we demonstrate that the recovery of the cell viability is obtained by inhibition of intrinsic apoptotic program, triggered by A-beta and involving caspase 9 and 3 activation. A protective role of insulin on mitochondrial damage is also shown by using Mito-red vital dye. Furthermore, A-beta activates the stress inducible Hsp70 protein in LAN5 cells and an overexpression is detectable after the addition of insulin, suggesting that this major induction is the necessary condition to activate a cell survival program. Together, these results may provide opportunities for the design of preventive and therapeutic strategies against AD.

  10. Nanoscale size dependence in the conjugation of amyloid beta and ovalbumin proteins on the surface of gold colloidal particles

    Energy Technology Data Exchange (ETDEWEB)

    Yokoyama, K; Briglio, N M; Hartati, D Sri; Tsang, S M W; MacCormac, J E; Welchons, D R [Department of Chemistry, State University of New York College at Geneseo, One College Circle, Geneseo, NY 14454 (United States)], E-mail: yokoyama@geneseo.edu

    2008-09-17

    Absorption spectroscopy was utilized to investigate the conjugation of amyloid {beta} protein solution (A{beta}{sub 1-40}) and chicken egg albumin (ovalbumin) with various sizes of gold colloidal nanoparticles for various pHs, ranging from pH 2 to pH 10. The pH value that indicates the colour change, pH{sub o}, exhibited colloidal size dependence for both A{beta}{sub 1-40} and ovalbumin coated particles. In particular, A{beta}{sub 1-40} coated gold colloidal particles exhibited non-continuous size dependence peaking at 40 and 80 nm, implying that their corresponding cage-like structures provide efficient net charge cancellation at these core sizes. Remarkably, only the pH{sub o} value for ovalbumin coated 80 nm gold colloid was pH>7, and a specific cage-like structure is speculated to have a positive net charge facing outward when ovalbumin self-assembles over this particular gold colloid. The previously reported reversible colour change between pH 4 and 10 took place only with A{beta}{sub 1-40} coated 20 nm gold colloids; this was also explored with ovalbumin coated gold colloids. Interestingly, gold colloidal nanoparticles showed a quasi-reversible colour change when they were coated with ovalbumin for all test sizes. The ovalbumin coated gold colloid was found to maintain reversible properties longer than A{beta}{sub 1-40} coated gold colloid.

  11. Accumulation of Exogenous Amyloid-Beta Peptide in Hippocampal Mitochondria Causes Their Dysfunction: A Protective Role for Melatonin

    Directory of Open Access Journals (Sweden)

    Sergio Rosales-Corral

    2012-01-01

    Full Text Available Amyloid-beta (Aβ pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS. Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer’s disease (AD brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.

  12. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model.

    Science.gov (United States)

    Puzzo, Daniela; Staniszewski, Agnieszka; Deng, Shi Xian; Privitera, Lucia; Leznik, Elena; Liu, Shumin; Zhang, Hong; Feng, Yan; Palmeri, Agostino; Landry, Donald W; Arancio, Ottavio

    2009-06-24

    Memory loss, synaptic dysfunction, and accumulation of amyloid beta-peptides (A beta) are major hallmarks of Alzheimer's disease (AD). Downregulation of the nitric oxide/cGMP/cGMP-dependent protein kinase/c-AMP responsive element-binding protein (CREB) cascade has been linked to the synaptic deficits after A beta elevation. Here, we report that the phosphodiesterase 5 inhibitor (PDE5) sildenafil (Viagra), a molecule that enhances phosphorylation of CREB, a molecule involved in memory, through elevation of cGMP levels, is beneficial against the AD phenotype in a mouse model of amyloid deposition. We demonstrate that the inhibitor produces an immediate and long-lasting amelioration of synaptic function, CREB phosphorylation, and memory. This effect is also associated with a long-lasting reduction of A beta levels. Given that side effects of PDE5 inhibitors are widely known and do not preclude their administration to a senile population, these drugs have potential for the treatment of AD and other diseases associated with elevated A beta levels.

  13. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

    Science.gov (United States)

    Zhao, Yanjun; Sivaji, Sivaprakash; Chiang, Michael C; Ali, Haadi; Zukowski, Monica; Ali, Sareen; Kennedy, Bryan; Sklyar, Alex; Cheng, Alice; Guo, Zihan; Reed, Alexander K; Kodali, Ravindra; Borowski, Jennifer; Frost, Georgia; Beukema, Patrick; Wills, Zachary P

    2017-10-11

    Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aβ activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aβ-NgR signaling, mediating Aβ's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

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    Niidome, Tetsuhiro, E-mail: tniidome@pharm.kyoto-u.ac.jp [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goh, Saori; Tanaka, Naoki [Department of Biomolecular Engineering, Kyoto Institute of Technology, Kyoto 606-8585 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kihara, Takeshi; Sugimoto, Hachiro [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  15. Icariin Prevents Amyloid Beta-Induced Apoptosis via the PI3K/Akt Pathway in PC-12 Cells

    Directory of Open Access Journals (Sweden)

    Dongdong Zhang

    2015-01-01

    Full Text Available Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum that exerts a variety of pharmacological activities and shows promise in the treatment and prevention of Alzheimer’s disease. In this study, we investigated the neuroprotective effects of icariin against amyloid beta protein fragment 25–35 (Aβ25–35 induced neurotoxicity in cultured rat pheochromocytoma PC12 cells and explored potential underlying mechanisms. Our results showed that icariin dose-dependently increased cell viability and decreased Aβ25–35-induced apoptosis, as assessed by MTT assay and Annexin V/propidium iodide staining, respectively. Results of western blot analysis revealed that the selective phosphatidylinositol 3-kinase (PI3K inhibitor LY294002 suppressed icariin-induced Akt phosphorylation, suggesting that the protective effects of icariin are associated with activation of the PI3K/Akt signaling pathway. LY294002 also blocked the icariin-induced downregulation of proapoptotic factors Bax and caspase-3 and upregulation of antiapoptotic factor Bcl-2 in Aβ25–35-treated PC12 cells. These findings provide further evidence for the clinical efficacy of icariin in the treatment of Alzheimer’s disease.

  16. Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity

    Directory of Open Access Journals (Sweden)

    Thomas J. Anastasio

    2014-05-01

    Full Text Available The leading hypothesis on Alzheimer Disease (AD is that it is caused by buildup of the peptide amyloid-beta (Abeta, which initially causes dysregulation of synaptic plasticity and eventually causes destruction of synapses and neurons. Pharmacological efforts to limit Abeta buildup have proven ineffective, and this raises the twin challenges of understanding the adverse effects of Abeta on synapses and of suggesting pharmacological means to prevent it. The purpose of this paper is to initiate a computational approach to understanding the dysregulation by Abeta of synaptic plasticity and to offer suggestions whereby combinations of various chemical compounds could be arrayed against it. This data-driven approach confronts the complexity of synaptic plasticity by representing findings from the literature in a course-grained manner, and focuses on understanding the aggregate behavior of many molecular interactions. The same set of interactions is modeled by two different computer programs, each written using a different programming modality: one imperative, the other declarative. Both programs compute the same results over an extensive test battery, providing an essential crosscheck. Then the imperative program is used for the computationally intensive purpose of determining the effects on the model of every combination of ten different compounds, while the declarative program is used to analyze model behavior using temporal logic. Together these two model implementations offer new insights into the mechanisms by which Abeta dysregulates synaptic plasticity and suggest many drug combinations that potentially may reduce or prevent it.

  17. Cholesterol enhances amyloid {beta} deposition in mouse retina by modulating the activities of A{beta}-regulating enzymes in retinal pigment epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jiying [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Ohno-Matsui, Kyoko, E-mail: k.ohno.oph@tmd.ac.jp [Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan); Morita, Ikuo [Section of Cellular Physiological Chemistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519 (Japan)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer Cholesterol-treated RPE produces more A{beta} than non-treated RPE. Black-Right-Pointing-Pointer Neprilysin expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer {alpha}-Secretase expression and activity decreased in cholesterol-treated RPE. Black-Right-Pointing-Pointer Cholesterol-enriched diet induced subRPE deposits in aged mice. Black-Right-Pointing-Pointer A{beta} were present in cholesterol-enriched-diet-induced subRPE deposits in aged mice. -- Abstract: Subretinally-deposited amyloid {beta} (A{beta}) is a main contributor of developing age-related macular degeneration (AMD). However, the mechanism causing A{beta} deposition in AMD eyes is unknown. Hypercholesterolemia is a significant risk for developing AMD. Thus, we investigated the effects of cholesterol on A{beta} production in retinal pigment epithelial (RPE) cells in vitro and in the mouse retina in vivo. RPE cells isolated from senescent (12-month-old) C57BL/6 mice were treated with 10 {mu}g/ml cholesterol for 48 h. A{beta} amounts in culture supernatants were measured by ELISA. Activity and expression of enzymes and proteins that regulate A{beta} production were examined by activity assay and real time PCR. The retina of mice fed cholesterol-enriched diet was examined by transmission electron microscopy. Cholesterol significantly increased A{beta} production in cultured RPE cells. Activities of A{beta} degradation enzyme; neprilysin (NEP) and anti-amyloidogenic secretase; {alpha}-secretase were significantly decreased in cell lysates of cholesterol-treated RPE cells compared to non-treated cells, but there was no change in the activities of {beta}- or {gamma}-secretase. mRNA levels of NEP and {alpha}-secretase (ADAM10 and ADAM17) were significantly lower in cholesterol-treated RPE cells than non-treated cells. Senescent (12-month-old) mice fed cholesterol-enriched chow developed subRPE deposits containing A{beta}, whereas

  18. Pharmacotherpy and Alzheimer's Disease: The M-Drugs (Melatonin, Minocycline, Modafinil, and Memantine) Approach.

    Science.gov (United States)

    Daulatzai, Mak Adam

    2016-01-01

    Despite advances in understanding the pathophysiology of Alzheimer's disease (AD), its therapy remains largely symptomatic and supportive. Acetylcholinesterase inhibitors - the first-line drugs used today do not prevent and treat AD. So far, over 90 Phase 3 trials of AD have been unsuccessful with 99.0% failure rate. There is, therefore, an urgent need to find effective new therapies for AD. Owing to the multifactorial nature of AD pathogenesis, polypharmacy with drugs that target heterogeneous pathophysiological pathways, needs to be considered. Fortunately, several drugs used currently in clinical use as monotherapies can be exploited in AD. This article, therefore, presents a novel pharmacological treatment paradigm and recommends the use of valuable diseasemodifying approved drugs, viz. melatonin, minocycline, modafinil, and memantine (the "M" Drugs). Melatonin - a neuroprotector is an antioxidant and anti-inflammatory. Minocycline is also neuroprotective, it reduces neuroinflammation and CNS pathology and prevents cell death. Sleep deprivation leads to decreased hippocampal neurogenesis, increased amyloid beta generation, and causes memory dysfunction. Modafinil - a wake-promoting agent is approved for use in narcolepsy and obstructive sleep apnea. It improves global mental status, hippocampal neurogenesis, attention, and cognition. Memantine is an uncompetitive N-methyl-d-aspartic acid receptor antagonist and is approved for the management of moderate-to-severe AD. The paramount possible beneficial effects of the M-drugs may include significant memory and cognitive enhancement in aging, mild cognitive impairment, and AD. The M drugs-centric pharmacotherapy strategy is comprehensive and pragmatic and is meant to combat multiple pathological targets and ameliorate cognitive dysfunction/AD.

  19. Reduced amyloidogenic processing of the amyloid beta-protein precursor by the small-molecule Differentiation Inducing Factor-1.

    Science.gov (United States)

    Myre, Michael A; Washicosky, Kevin; Moir, Robert D; Tesco, Giuseppina; Tanzi, Rudolph E; Wasco, Wilma

    2009-04-01

    The detection of cell cycle proteins in Alzheimer's disease (AD) brains may represent an early event leading to neurodegeneration. To identify cell cycle modifiers with anti-Abeta properties, we assessed the effect of Differentiation-Inducing Factor-1 (DIF-1), a unique, small-molecule from Dictyostelium discoideum, on the proteolysis of the amyloid beta-protein precursor (APP) in a variety of different cell types. We show that DIF-1 slows cell cycle progression through G0/G1 that correlates with a reduction in cyclin D1 protein levels. Western blot analysis of DIF-treated cells and conditioned medium revealed decreases in the levels of secreted APP, mature APP, and C-terminal fragments. Assessment of conditioned media by sandwich ELISA showed reduced levels of Abeta40 and Abeta42, also demonstrating that treatment with DIF-1 effectively decreases the ratio of Abeta42 to Abeta40. In addition, DIF-1 significantly diminished APP phosphorylation at residue T668. Interestingly, site-directed mutagenesis of APP residue Thr668 to alanine or glutamic acid abolished the effect of DIF-1 on APP proteolysis and restored secreted levels of Abeta. Finally, DIF-1 prevented the accumulation of APP C-terminal fragments induced by the proteasome inhibitor lactacystin, and calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN). Our findings suggest that DIF-1 affects G0/G1-associated amyloidogenic processing of APP by a gamma-secretase-, proteasome- and calpain-insensitive pathway, and that this effect requires the presence of residue Thr668.

  20. Repair of amyloid beta(25-35)-induced memory impairment and synaptic loss by a Kampo formula, Zokumei-to.

    Science.gov (United States)

    Tohda, Chihiro; Tamura, Takayuki; Komatsu, Katsuko

    2003-11-14

    Although Zokumei-to (ZMT), a Kampo formula, has been used for postapopletic sequelae such as paralysis and logopathy, only few studies of this drug have been carried out. We hypothesized that ZMT may affect neuronal plasticity and investigated whether or not this drug is capable of improving learning impairment and synaptic loss observed in patients with Alzheimer's disease (AD). Amyloid beta(25-35) [Abeta(25-35)] (4.7 nmol) was intracerebroventricularly injected into ddY mice (male, 6 weeks old). Fourteen days after the injection, mice were given ZMT extract (500 mg/kg/day) per os for 15 days. In a memory acquisition test, the Abeta(25-35)-injected mice required more time to master this task than did mice in the saline- or reverse peptide Abeta(35-25)-treated groups. ZMT-treated mice shortened escape latencies during trial days 3-5, but not significantly. Three days after the last drug treatment, a retention test was performed. Following ZMT, the number of crossings over a platform was significantly decreased in Abeta(25-35)-injected mice compared with those in the control groups. However, ZMT-treated mice showed complete recovery of this number. Although Abeta(25-35) injection decreased synaptophysin expression in the cerebral cortex and the hippocampus, ZMT treatment significantly increased the level of expression of synaptophysin up to the control level. Donepezil hydrochloride (DNP, 0.5 mg/kg/day, p.o.) clinically used for AD had no effect on memory retention and synaptophysin levels. Abeta(25-35)-induced neuronal loss was not observed in any region of the brain. The present results suggest that memory impairment and synaptic loss in AD patients may be improved by treatment with ZMT, even after such impairment has already progressed.

  1. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

    Science.gov (United States)

    Fleisher, Adam S; Raman, Rema; Siemers, Eric R; Becerra, Lida; Clark, Christopher M; Dean, Robert A; Farlow, Martin R; Galvin, James E; Peskind, Elaine R; Quinn, Joseph F; Sherzai, Abdullah; Sowell, B Brooke; Aisen, Paul S; Thal, Leon J

    2008-08-01

    To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.

  2. Phase II safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer's disease

    Science.gov (United States)

    Fleisher, Adam S.; Raman, Rema; Siemers, Eric R.; Becerra, Lida; Clark, Christopher M.; Dean, Robert A; Farlow, Martin R.; Galvin, James E.; Peskind, Elaine R.; Quinn, Joseph F.; Sherzai, Abdullah; Sowell, B. Brooke; Aisen, Paul S.; Thal, Leon J.

    2009-01-01

    Objective Evaluate the safety, tolerability and amyloid beta (Aβ) response to a γ-secretase inhibitor (LY450139) in Alzheimer's disease. Design Multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial. Setting Community based clinical research centers. Participants 51 participants with mild to moderate AD were randomized (placebo=15, 100mg=22, 140mg=14), with 43 completing the treatment phase. Intervention Subjects randomized to LY450139 received 60mg daily for 2 weeks followed by 100mg for 6 weeks, then re-randomized to 100mg or 140mg for 6 additional weeks. Main Outcome Measures Primary outcome measures consisted of adverse events, plasma and cerebrospinal fluid Aβ levels, vital signs, electrocardiogram data, and laboratory safety tests. Secondary outcome measures included the ADAS-cognitive subscale and the ADCS-Activities of Daily Living scale. Results Group differences were seen in “skin and subcutaneous tissue” complaints (p=0.052). These included 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse-event-related discontinuations, including one report of transient bowel obstruction. Plasma Aβ40 was reduced by 58.2% for the 100mg group and 64.6% for the 140mg group (P<0.001). No significant reduction was seen in CSF Aβ. No group differences were seen in cognitive or functional measures. Conclusions LY450139 was generally well tolerated at doses of up to 140mg taken daily for 14 weeks with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Aβ concentrations were consistent with inhibition of γ-secretase. PMID:18695053

  3. Alzheimer's Toxic Amyloid Beta Oligomers: Unwelcome Visitors to the Na/K ATPase alpha3 Docking Station.

    Science.gov (United States)

    DiChiara, Thomas; DiNunno, Nadia; Clark, Jeffrey; Bu, Riana Lo; Cline, Erika N; Rollins, Madeline G; Gong, Yuesong; Brody, David L; Sligar, Stephen G; Velasco, Pauline T; Viola, Kirsten L; Klein, William L

    2017-03-01

    Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death. Memory loss and pathology in transgenic models are prevented by AβO antibodies, while Aducanumab, an antibody that targets AβOs as well as fibrillar Aβ, has provided cognitive benefit to humans in early clinical trials. AβOs have now been investigated in more than 3000 studies and are widely thought to be the major toxic form of Aβ. Although much has been learned about the downstream mechanisms of AβO action, a major gap concerns the earliest steps: How do AβOs initially interact with surface membranes to generate neuron-damaging transmembrane events? Findings from Ohnishi et al (PNAS 2005) combined with new results presented here are consistent with the hypothesis that AβOs act as neurotoxins because they attach to particular membrane protein docks containing Na/K ATPase-α3, where they inhibit ATPase activity and pathologically restructure dock composition and topology in a manner leading to excessive Ca++ build-up. Better understanding of the mechanism that makes attachment of AβOs to vulnerable neurons a neurotoxic phenomenon should open the door to therapeutics and diagnostics targeting the first step of a complex pathway that leads to neural damage and dementia.

  4. Nanoformulated alpha-mangostin ameliorates Alzheimer's disease neuropathology by elevating LDLR expression and accelerating amyloid-beta clearance.

    Science.gov (United States)

    Yao, Lei; Gu, Xiao; Song, Qingxiang; Wang, Xiaolin; Huang, Meng; Hu, Meng; Hou, Lina; Kang, Ting; Chen, Jun; Chen, Hongzhuan; Gao, Xiaoling

    2016-03-28

    Alzheimer's disease (AD), the most common form of dementia, is now representing one of the largest global healthcare challenges. However, an effective therapy is still lacking. Accumulation of amyloid-beta (Aβ) in the brain is supposed to trigger pathogenic cascades that eventually lead to AD. Therefore, Aβ clearance strategy is being actively pursued as a promising disease modifying therapy. Here, we found that α-mangostin (α-M), a polyphenolic xanthone derivative from mangosteen, up-regulated low density lipoprotein receptor (LDLR) expression in microglia and liver cells, and efficiently facilitated Aβ clearance. However, the in vivo application of α-M is limited due to its hydrophobic nature, poor aqueous solubility and stability, and thus low bioavailability and accumulation in the target organs. To overcome this limitation, α-M was encapsulated into the core of poly(ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(α-M)]. Such nanoencapsulation improved the biodistribution of α-M in both the brain and liver, enhanced the brain clearance of (125)I-radiolabeled Aβ1-42 in an LDLR-dependent manner, reduced Aβ deposition, attenuated neuroinflammatory responses, ameliorated neurologic changes and reversed behavioral deficits in AD model mice. These findings justified the concept that polyphenol-mediated modulation of LDLR expression might serve as a safe and efficient disease-modifying therapy for AD by accelerating Aβ clearance. It also demonstrated the powerful capacity of nanotechnology in modulating the biodistribution behavior of drug to improve its therapeutic efficacy in AD. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice.

    Science.gov (United States)

    He, Xiao-Fei; Liu, Dong-Xu; Zhang, Qun; Liang, Feng-Ying; Dai, Guang-Yan; Zeng, Jin-Sheng; Pei, Zhong; Xu, Guang-Qing; Lan, Yue

    2017-01-01

    Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood-brain barrier (BBB) or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF) and the interstitial fluid (ISF). A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer's disease (AD), but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4), astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ) were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA); synaptic function was investigated with Thy1 -green fluorescent protein (GFP) transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95) increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition. These data suggest

  6. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice

    Directory of Open Access Journals (Sweden)

    Xiao-fei He

    2017-05-01

    Full Text Available Age is characterized by chronic inflammation, leading to synaptic dysfunction and dementia because the clearance of protein waste is reduced. The clearance of proteins depends partly on the permeation of the blood–brain barrier (BBB or on the exchange of water and soluble contents between the cerebrospinal fluid (CSF and the interstitial fluid (ISF. A wealth of evidence indicates that physical exercise improves memory and cognition in neurodegenerative diseases during aging, such as Alzheimer’s disease (AD, but the influence of physical training on glymphatic clearance, BBB permeability and neuroinflammation remains unclear. In this study, glymphatic clearance and BBB permeability were evaluated in aged mice using in vivo two-photon imaging. The mice performed voluntary wheel running exercise and their water-maze cognition was assessed; the expression of the astrocytic water channel aquaporin 4 (AQP4, astrocyte and microglial activation, and the accumulation of amyloid beta (Aβ were evaluated with immunofluorescence or an enzyme-linked immunosorbent assay (ELISA; synaptic function was investigated with Thy1–green fluorescent protein (GFP transgenic mice and immunofluorescent staining. Voluntary wheel running significantly improved water-maze cognition in the aged mice, accelerated the efficiency of glymphatic clearance, but which did not affect BBB permeability. The numbers of activated astrocytes and microglia decreased, AQP4 expression increased, and the distribution of astrocytic AQP4 was rearranged. Aβ accumulation decreased, whereas dendrites, dendritic spines and postsynaptic density protein (PSD95 increased. Our study suggests that voluntary wheel running accelerated glymphatic clearance but not BBB permeation, improved astrocytic AQP4 expression and polarization, attenuated the accumulation of amyloid plaques and neuroinflammation, and ultimately protected mice against synaptic dysfunction and a decline in spatial cognition

  7. Cortical Amyloid Beta in Cognitively Normal Elderly Adults is Associated with Decreased Network Efficiency within the Cerebro-Cerebellar System.

    Science.gov (United States)

    Steininger, Stefanie C; Liu, Xinyang; Gietl, Anton; Wyss, Michael; Schreiner, Simon; Gruber, Esmeralda; Treyer, Valerie; Kälin, Andrea; Leh, Sandra; Buck, Alfred; Nitsch, Roger M; Prüssmann, Klaas P; Hock, Christoph; Unschuld, Paul G

    2014-01-01

    Deposition of cortical amyloid beta (Aβ) is a correlate of aging and a risk factor for Alzheimer disease (AD). While several higher order cognitive processes involve functional interactions between cortex and cerebellum, this study aims to investigate effects of cortical Aβ deposition on coupling within the cerebro-cerebellar system. We included 15 healthy elderly subjects with normal cognitive performance as assessed by neuropsychological testing. Cortical Aβ was quantified using (11)carbon-labeled Pittsburgh compound B positron-emission-tomography late frame signals. Volumes of brain structures were assessed by applying an automated parcelation algorithm to three dimensional magnetization-prepared rapid gradient-echo T1-weighted images. Basal functional network activity within the cerebro-cerebellar system was assessed using blood-oxygen-level dependent resting state functional magnetic resonance imaging at the high field strength of 7 T for measuring coupling between cerebellar seeds and cerebral gray matter. A bivariate regression approach was applied for identification of brain regions with significant effects of individual cortical Aβ load on coupling. Consistent with earlier reports, a significant degree of positive and negative coupling could be observed between cerebellar seeds and cerebral voxels. Significant positive effects of cortical Aβ load on cerebro-cerebellar coupling resulted for cerebral brain regions located in inferior temporal lobe, prefrontal cortex, hippocampus, parahippocampal gyrus, and thalamus. Our findings indicate that brain amyloidosis in cognitively normal elderly subjects is associated with decreased network efficiency within the cerebro-cerebellar system. While the identified cerebral regions are consistent with established patterns of increased sensitivity for Aβ-associated neurodegeneration, additional studies are needed to elucidate the relationship between dysfunction of the cerebro-cerebellar system and risk for AD.

  8. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease

    DEFF Research Database (Denmark)

    Jensen, Camilla Steen; Portelius, Erik; Siersma, Volkert

    2016-01-01

    Background: Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical...... of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients...

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

    Directory of Open Access Journals (Sweden)

    Hye Youn Sung

    Full Text Available 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 HMOX1 expression. 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

  10. Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1{alpha}, suppress amyloid {beta}-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Dayanidhi; Milatovic, Snjezana-Zaja [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Milatovic, Dejan [Department of Pediatrics/Pediatric Toxicology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Splittgerber, Ryan [Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States); Fan, Guo-Huang [Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37221 (United States); Richmond, Ann, E-mail: ann.richmond@vanderbilt.edu [VA Medical Center, Nashville, TN 37232 (United States); Department of Cancer Biology, Vanderbilt University, School of Medicine, Nashville, TN 37232 (United States)

    2011-11-15

    Alzheimer's disease (AD) is characterized by a progressive cognitive decline and accumulation of neurotoxic oligomeric peptides amyloid-{beta} (A{beta}). Although the molecular events are not entirely known, it has become evident that inflammation, environmental and other risk factors may play a causal, disruptive and/or protective role in the development of AD. The present study investigated the ability of the chemokines, macrophage inflammatory protein-2 (MIP-2) and stromal cell-derived factor-1{alpha} (SDF-1{alpha}), the respective ligands for chemokine receptors CXCR2 and CXCR4, to suppress A{beta}-induced neurotoxicity in vitro and in vivo. Pretreatment with MIP-2 or SDF-1{alpha} significantly protected neurons from A{beta}-induced dendritic regression and apoptosis in vitro through activation of Akt, ERK1/2 and maintenance of metalloproteinase ADAM17 especially with SDF-1{alpha}. Intra-cerebroventricular (ICV) injection of A{beta} led to reduction in dendritic length and spine density of pyramidal neurons in the CA1 area of the hippocampus and increased oxidative damage 24 h following the exposure. The A{beta}-induced morphometric changes of neurons and increase in biomarkers of oxidative damage, F{sub 2}-isoprostanes, were significantly inhibited by pretreatment with the chemokines MIP-2 or SDF-1{alpha}. Additionally, MIP-2 or SDF-1{alpha} was able to suppress the aberrant mislocalization of p21-activated kinase (PAK), one of the proteins involved in the maintenance of dendritic spines. Furthermore, MIP-2 also protected neurons against A{beta} neurotoxicity in CXCR2-/- mice, potentially through observed up regulation of CXCR1 mRNA. Understanding the neuroprotective potential of chemokines is crucial in defining the role for their employment during the early stages of neurodegeneration. -- Research highlights: Black-Right-Pointing-Pointer Neuroprotective ability of the chemokines MIP2 and CXCL12 against A{beta} toxicity. Black-Right-Pointing-Pointer MIP

  11. Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation

    Directory of Open Access Journals (Sweden)

    Podlisny Marcia

    2011-01-01

    Full Text Available Abstract Background Previously we reported 1 μM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. Results Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50 in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aβd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state, lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aβ monomers are not active, suggesting oxidized SDS-stable Aβ1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Conclusions Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.

  12. PET studies of {sup 18}F-memantine in healthy volunteers

    Energy Technology Data Exchange (ETDEWEB)

    Ametamey, S.M. E-mail: simon-mensah.ametamey@psi.ch; Bruehlmeier, M.; Kneifel, S.; Kokic, M.; Honer, M.; Arigoni, M.; Buck, A.; Burger, C.; Samnick, S.; Quack, G.; Schubiger, P.A

    2002-02-01

    Previous studies in mice and PET investigations in a Rhesus monkey showed that the regional uptake of {sup 18}F-memantine could be blocked by pharmacological doses of memantine and (+)-MK-801. In the present study, the binding characteristics of {sup 18}F-memantine was examined in five healthy volunteers. In humans, {sup 18}F-memantine was homogeneously distributed in gray matter i.e. cortex and basal ganglia regions, as well as the cerebellum. No radioactive metabolites were detected in plasma during the time-frame of the PET studies. The uptake of {sup 18}F-memantine in receptor-rich regions such as striatum and frontal cortex could be well described by a 1-tissue compartment model. The DV'' values of all gray matter regions were similar and ranged from 15 to 20 ml/ml. The white matter showed lower DV'' values of 15 {+-} 1.4 ml/ml. These results suggest that {sup 18}F-memantine distribution in human brain does not reflect the regional NMDA receptor concentration, and therefore, this radioligand is not suitable for the PET imaging of the NMDA receptors.

  13. Reducing the Levels of Akt Activation by PDK1 Knock-in Mutation Protects Neuronal Cultures against Synthetic Amyloid-Beta Peptides

    Directory of Open Access Journals (Sweden)

    Shaobin Yang

    2018-01-01

    Full Text Available The Akt kinase has been widely assumed for years as a key downstream effector of the PI3K signaling pathway in promoting neuronal survival. This notion was however challenged by the finding that neuronal survival responses were still preserved in mice with reduced Akt activity. Moreover, here we show that the Akt signaling is elevated in the aged brain of two different mice models of Alzheimer Disease. We manipulate the rate of Akt stimulation by employing knock-in mice expressing a mutant form of PDK1 (phosphoinositide-dependent protein kinase 1 with reduced, but not abolished, ability to activate Akt. We found increased membrane localization and activity of the TACE/ADAM17 α-secretase in the brain of the PDK1 mutant mice with concomitant TNFR1 processing, which provided neurons with resistance against TNFα-induced neurotoxicity. Opposite to the Alzheimer Disease transgenic mice, the PDK1 knock-in mice exhibited an age-dependent attenuation of the unfolding protein response, which protected the mutant neurons against endoplasmic reticulum stressors. Moreover, these two mechanisms cooperatively provide the mutant neurons with resistance against amyloid-beta oligomers, and might singularly also contribute to protect these mice against amyloid-beta pathology.

  14. Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial.

    Directory of Open Access Journals (Sweden)

    Chris Fox

    Full Text Available Agitation in Alzheimer's disease (AD is common and associated with poor patient life-quality and carer distress. The best evidence-based pharmacological treatments are antipsychotics which have limited benefits with increased morbidity and mortality. There are no memantine trials in clinically significant agitation but post-hoc analyses in other populations found reduced agitation. We tested the primary hypothesis, memantine is superior to placebo for clinically significant agitation, in patients with moderate-to-severe AD.We recruited 153 participants with AD and clinically significant agitation from care-homes or hospitals for a double-blind randomised-controlled trial and 149 people started the trial of memantine versus placebo. The primary outcome was 6 weeks mixed model autoregressive analysis of Cohen-Mansfield Agitation Inventory (CMAI. Secondary outcomes were: 12 weeks CMAI; 6 and 12 weeks Neuropsychiatric symptoms (NPI, Clinical Global Impression Change (CGI-C, Standardised Mini Mental State Examination, Severe Impairment Battery. Using a mixed effects model we found no significant differences in the primary outcome, 6 weeks CMAI, between memantine and placebo (memantine lower -3.0; -8.3 to 2.2, p = 0.26; or 12 weeks CMAI; or CGI-C or adverse events at 6 or 12 weeks. NPI mean difference favoured memantine at weeks 6 (-6.9; -12.2 to -1.6; p = 0.012 and 12 (-9.6; -15.0 to -4.3 p = 0.0005. Memantine was significantly better than placebo for cognition. The main study limitation is that it still remains to be determined whether memantine has a role in milder agitation in AD.Memantine did not improve significant agitation in people with in moderate-to-severe AD. Future studies are urgently needed to test other pharmacological candidates in this group and memantine for neuropsychiatric symptoms.ClinicalTrials.gov NCT00371059.International Standard Randomised Controlled Trial 24953404.

  15. Clinical Benefits of Memantine Treatment for Alzheimer's Disease in the Okayama Memantine Study II (OMS II).

    Science.gov (United States)

    Matsuzono, Kosuke; Yamashita, Toru; Ohta, Yasuyuki; Hishikawa, Nozomi; Koike, Makoto; Sato, Kota; Kono, Syoichiro; Deguchi, Kentaro; Nakano, Yumiko; Abe, Koji

    2015-01-01

    The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.

  16. Amyloid-beta (25-35) peptide induces the release of pro-matrix metalloprotease 9 (pro-MMP-9) from human neutrophils.

    Science.gov (United States)

    Achilli, Cesare; Ciana, Annarita; Minetti, Giampaolo

    2014-12-01

    Alzheimer's disease (AD) is a degenerative process of the brain, leading to increasing impairment of cognitive functions, and is associated with accumulation in the brain of several amyloid-beta (Aβ) peptides (as amyloid plaques), including Aβ25-35. Neutrophils, the most abundant immune cell type infiltrated in the brain of AD patients, accumulate behind amyloid plaques. Aβ peptides can trigger activation of chemotaxis and oxidative burst in neutrophils, suggesting a role in modulating the neuroinflammation process. We have shown that Aβ25-35 can induce the release from human neutrophils of pro-MMP-9, a metalloprotease involved in the onset of inflammation, corroborating the hypothesis of the involvement of infiltrated neutrophils in the inflammatory processes, which occur in the AD brain.

  17. Antibody responses, amyloid-beta peptide remnants and clinical effects of AN-1792 immunization in patients with AD in an interrupted trial.

    Science.gov (United States)

    Kokjohn, Tyler A; Roher, Alex E

    2009-04-01

    Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-beta (Abeta) 40/42 increased in the gray matter compared to sporadic Alzheimer's disease (AD) patients and total brain Abeta levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular amyloid and hyper-phosphorylated tau deposits appeared refractory to this therapy. In addition, vaccination resulted in the consequential and drastic expansion of the white matter (WM) amyloid pool to levels without precedent in sporadic AD patients. Although vaccination disrupted amyloid plaques, this therapy did not enhance long-term cognitive function or necessarily halt neurodegeneration. The intricate involvement of vascular pathology in AD evolution and the firm recalcitrance of vessel-associated amyloid to antibody-mediated disruption suggest that immunization therapies might be more effective if administered on a prophylactic basis before vascular impairment and well ahead of any clinically evident cognitive decline. Amyloid-beta is viewed as pathological based on the postmortem correlation of senile plaques with an AD diagnosis. It remains uncertain which of the various forms of this peptide is the most toxic and whether Abeta or senile plaques themselves serve any desirable or protective functions. The long-term cognitive effects of chronic immunotherapy producing a steadily accumulating and effectively permanent pool of disrupted Abeta peptides within the human brain are unknown. In addition, the side effects of such therapy provided on a chronic basis could extend far beyond the brain. Eagerly seeking new therapies, critical knowledge gaps should prompt us to take a more wholistic perspective viewing Abeta and the amyloid cascade as aspects of complex

  18. Memantine for treatment of moderate or severe Alzheimer's disease patients in urban China: clinical and economic outcomes from a health economic model.

    Science.gov (United States)

    Hu, Shanlian; Yu, Xin; Chen, Shengdi; Clay, Emilie; Toumi, Mondher; Milea, Dominique

    2015-01-01

    To estimate the clinical and economic benefits of memantine treatment initiated in moderate Alzheimer's disease (AD) in China, compared with initiation in severe AD only. A Markov model with a 5-year time horizon simulated moderate patients' progression through health states. Two groups were compared: patients receiving memantine from the moderate stage (i.e., at model entry), continuing treatment when reaching the severe stage; patients initiating memantine only when they developed severe disease. After 5 years, fewer patients receiving memantine from the moderate stage were severe (49%), dependent (59%) or aggressive (47%) compared with moderate patients who initiated treatment from severe stage only (58, 67 and 55%, respectively). Total cost of care was lower for treatment from moderate stage (67 billion RMB) when compared with treatment from severe stage (73 billion RMB). In China, AD treatment with memantine from the moderate stage could result in substantial cost savings.

  19. Dual Targeting of Amyloid-beta Clearance and Neuroinflammation as a Novel Therapeutic Approach against Alzheimer's Disease

    Science.gov (United States)

    Batarseh, Yazan S.

    Amyloid-beta (Abeta) cascade hypothesis suggests that Alzheimer's disease (AD) is related to an imbalance between the production and clearance of Abeta peptide. Sporadic AD has been related to faulty clearance of Abeta. Accumulation of Abeta oligomers (Abetao) has been linked to several downstream toxic effects including neuroinflammation, synaptic loss, and cellular death. Abeta transport across the blood-brain barrier (BBB) is one of the primary pathways for reducing Abeta load in the brain, which work hand in hand with other parenchymal mechanisms to reduce Abeta levels including intra and extracellular degradation by a family of Abeta degrading enzymes. Established AD drugs, such as the cholinesterase inhibitor donepezil, have been reported to have several additional non-cholinergic effects that alter Abeta pathology; reduce Abeta load, anti-inflammatory response, and attenuate synaptic loss. However, their limited effect only lead to minor improvements in AD symptoms without improving the prognosis of the disease. The lack of effective medical treatment for AD led to several studies focusing on establishing new therapeutic approaches to reduce Abeta pathology. We aimed to identify and characterize natural products that are capable of enhancing the BBB clearance of Abeta in addition to reducing neuroinflammation. Our first project was to investigate the role of oleocanthal (one of the active ingredients in extra-virgin olive oil; EVOO) on attenuating Abeta toxic effects on neurons and astrocytes. We developed Abeta oligomers (Abetao) induced inflammatory environment by exposing neurons and astrocytes to accumulative doses of Abetao to investigate oleocanthal effect on modulating Abetao pathological changes in neurons and astrocytes. Our findings demonstrated oleocanthal prevented Abetao-induced synaptic proteins, SNAP-25 and PSD-95, down-regulation in neurons, attenuated Abetao-induced inflammation, and restored glutamine transporter (GLT1) and glucose

  20. CD147 is a regulatory subunit of the gamma-secretase complex inAlzheimer's disease amyloid beta-peptide production

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    Zhou, Shuxia; Zhou, Hua; Walian, Peter J.; Jap, Bing K.

    2005-04-06

    {gamma}-secretase is a membrane protein complex that cleaves the {beta}-amyloid precursor protein (APP) within the transmembrane region, following prior processing by {beta}-secretase, producing amyloid {beta}-peptides (A{beta}{sub 40} and A{beta}{sub 42}). Errant production of A{beta}-peptides that substantially increases A{beta}{sub 42} production has been associated with the formation of amyloid plaques in Alzheimer's disease patients. Biophysical and genetic studies indicate that presenilin-1 (Psn-1), which contains the proteolytic active site, and three other membrane proteins, nicastrin (Nct), APH-1, and PEN-2 are required to form the core of the active {gamma}-secretase complex. Here, we report the purification of the native {gamma}-secretase complexes from HeLa cell membranes and the identification of an additional {gamma}-secretase complex subunit, CD147, a transmembrane glycoprotein with two immunoglobulin-like domains. The presence of this subunit as an integral part of the complex itself was confirmed through co-immunoprecipitation studies of the purified protein from HeLa cells and solubilized complexes from other cell lines such as neural cell HCN-1A and HEK293. Depletion of CD147 by RNA interference was found to increase the production of A{beta} peptides without changing the expression level of the other {gamma}-secretase components or APP substrates while CD147 overexpression had no statistically significant effect on amyloid {beta}-peptide production, other {gamma}-secretase components or APP substrates, indicating that the presence of the CD147 subunit within the {gamma}-secretase complex directly down-modulates the production of A{beta}-peptides. {gamma}-secretase was first recognized through its role in the production of the A{beta} peptides that are pathogenic in Alzheimer's disease (AD) (1). {gamma}-secretase is a membrane protein complex with unusual aspartyl protease activity that cleaves a variety of type I membrane proteins

  1. Memantine

    Science.gov (United States)

    ... AD; a brain disease that slowly destroys the memory and the ability to think, learn, communicate and ... is important to keep all medication out of sight and reach of children as many containers (such ...

  2. Effect of ionic strength on the aggregation kinetics of the amidated amyloid beta peptide Aβ (1-40) in aqueous solutions.

    Science.gov (United States)

    Campos-Ramírez, Adriana; Márquez, Maripaz; Quintanar, Liliana; Rojas-Ochoa, Luis F

    2017-09-01

    In this work we study the effect of solution ionic strength on the structural evolution of amidated amyloid beta peptide Aβ (1-40) oligomers at the early stages of fibril formation. By light scattering, we follow the time evolution of the structure and short-time dynamics of peptide structures at low ionic strengths. Our results allow identifying initial oligomer structures as the effective building blocks in the amyloid fibrils formation and indicate that the oligomers growth pathway, from compact structures to flexible chain-like structures, becomes faster as the solution ionic strength is increased. Furthermore, we find no evidence of structural branching what suggests that elongation of amyloid fibrils is dominated by linear association. To describe our results we adapt a phenomenological model based on population balance equations and linear polymer growth, where the parameters required are obtained from the experiments. Model calculations are in good agreement with experimentally-obtained estimates for the radius of gyration of Aβ (1-40) oligomers, thus further supporting our findings. Additionally, we introduce a model for the effective interaction among initial Aβ structures that captures the dependence of the effective association rates on solution ionic strength. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Pelargonidin Improves Passive Avoidance Task Performance in a Rat Amyloid Beta25-35 Model of Alzheimer’s Disease Via Estrogen Receptor Independent Pathways

    Directory of Open Access Journals (Sweden)

    Hamid Sohanaki

    2016-05-01

    Full Text Available Alzheimer’s disease (AD is a disorder with multiple pathophysiological causes, destructive outcomes, and no available definitive cure. Pelargonidin (Pel, an anthocyanin derivative, is an estrogen receptor agonist with little estrogen side effects. This study was designed to assess Pel memory enhancing effects on the a rat Amyloid Beta25-35 (Aβ intrahippocampal microinjections model of AD in the passive avoidance task performance paradigm and further evaluate the potential estrogen receptor role on the memory-evoking compound. Equally divided rats were assigned to 5 groups of sham, Aβ intrahippocampal microinjected, Pel pretreated (10 mg/kg; P.O, α estrogen antagonist intra-cerebrovascular (i.c.v. microinjected, and β estrogen antagonist (i.c.v microinjected animals. Intrahippocampal microinjections of Aβ were adopted to provoke AD model. Passive avoidance task test was also used to assess memory performance. Pel pretreatment prior to Aβ microinjections significantly improved step-through latency (P<0.001 in passive avoidance test. In α and β estrogen, antagonists received animals, passive avoidance task performance was not statistically changed (P=0.11 & P=0.41 respectively compared to Pel pretreated and sham animals. Our results depicted that Pel improves Aβ induced memory dysfunction in passive avoidance test performance through estrogen receptor independently related pathways.

  4. Amyloid-beta 1-40 is associated with alterations in NG2+ pericyte population ex vivo and in vitro.

    Science.gov (United States)

    Schultz, Nina; Brännström, Kristoffer; Byman, Elin; Moussaud, Simon; Nielsen, Henrietta M; Olofsson, Anders; Wennström, Malin

    2018-02-17

    The population of brain pericytes, a cell type important for vessel stability and blood brain barrier function, has recently been shown altered in patients with Alzheimer's disease (AD). The underlying reason for this alteration is not fully understood, but progressive accumulation of the AD characteristic peptide amyloid-beta (Aβ) has been suggested as a potential culprit. In the current study, we show reduced number of hippocampal NG2+ pericytes and an association between NG2+ pericyte numbers and Aβ1-40 levels in AD patients. We further demonstrate, using in vitro studies, an aggregation-dependent impact of Aβ1-40 on human NG2+ pericytes. Fibril-EP Aβ1-40 exposure reduced pericyte viability and proliferation and increased caspase 3/7 activity. Monomer Aβ1-40 had quite the opposite effect: increased pericyte viability and proliferation and reduced caspase 3/7 activity. Oligomer-EP Aβ1-40 had no impact on either of the cellular events. Our findings add to the growing number of studies suggesting a significant impact on pericytes in the brains of AD patients and suggest different aggregation forms of Aβ1-40 as potential key regulators of the brain pericyte population size. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  5. Aniracetam restores the effects of amyloid-beta protein or ageing on membrane fluidity and intracellular calcium concentration in mice synaptosomes.

    Science.gov (United States)

    Li, Y; Wang, J-J; Cai, J-X

    2007-01-01

    In the present study, we observed the in vitro effect of aniracetam on membrane fluidity and free calcium concentrations ([Ca(2+)]i) of frontal cortical (FC) and hippocampal (HP) synaptosomes of aged mice and young mice treated with amyloid-beta protein (Abeta) Membrane fluidity was measured by using fluorescence anisotropy of the lipophilic probe, 1,6-diphenyl-1,3,5-hexatriene (DPH). [Ca(2+)]i was measured by using Fura 2-AM fluorescent spectrophotometry. We found that membrane fluidity of the FC and HP synaptosomes was decreased in 14 months old mice compared with that in 3 months old mice. Similarly, Abeta25-35 (1 microM) decreased the membrane fluidity in 3 months old mice. These effects of ageing and Abeta25-35 on membrane fluidity were restored by aniracetam in a concentration-dependent manner. Furthermore, Abeta25-35 (1 microM) largely increased [Ca(2+)]i in FC and HP synaptosomes in 3 months old mice, but this effect on HP synaptosomes was effectively reversed by aniracetam (1-4 mM). The present findings suggest that aniracetam restores age- and Abeta-induced alterations in membrane fluidity or Abeta-induced increase in [Ca(2+)]i, demonstrating a possible beneficial role of aniracetam in the clinic treatment for senile dementia or Alzheimer's disease.

  6. Amyloid beta and the longest-lived rodent: the naked mole-rat as a model for natural protection from Alzheimer's disease.

    Science.gov (United States)

    Edrey, Yael H; Medina, David X; Gaczynska, Maria; Osmulski, Pawel A; Oddo, Salvatore; Caccamo, Antonella; Buffenstein, Rochelle

    2013-10-01

    Amyloid beta (Aβ) is implicated in Alzheimer's disease (AD) as an integral component of both neural toxicity and plaque formation. Brains of the longest-lived rodents, naked mole-rats (NMRs) approximately 32 years of age, had levels of Aβ similar to those of the 3xTg-AD mouse model of AD. Interestingly, there was no evidence of extracellular plaques, nor was there an age-related increase in Aβ levels in the individuals examined (2-20+ years). The NMR Aβ peptide showed greater homology to the human sequence than to the mouse sequence, differing by only 1 amino acid from the former. This subtle difference led to interspecies differences in aggregation propensity but not neurotoxicity; NMR Aβ was less prone to aggregation than human Aβ. Nevertheless, both NMR and human Aβ were equally toxic to mouse hippocampal neurons, suggesting that Aβ neurotoxicity and aggregation properties were not coupled. Understanding how NMRs acquire and tolerate high levels of Aβ with no plaque formation could provide useful insights into AD, and may elucidate protective mechanisms that delay AD progression. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Antiamnesic Effect of Broccoli (Brassica oleracea var. italica) Leaves on Amyloid Beta (Aβ)1-42-Induced Learning and Memory Impairment.

    Science.gov (United States)

    Park, Seon Kyeong; Ha, Jeong Su; Kim, Jong Min; Kang, Jin Yong; Lee, Du Sang; Guo, Tian Jiao; Lee, Uk; Kim, Dae-Ok; Heo, Ho Jin

    2016-05-04

    To examine the antiamnesic effects of broccoli (Brassica oleracea var. italica) leaves, we performed in vitro and in vivo tests on amyloid beta (Aβ)-induced neurotoxicity. The chloroform fraction from broccoli leaves (CBL) showed a remarkable neuronal cell-protective effect and an inhibition against acetylcholinesterase (AChE). The ameliorating effect of CBL on Aβ1-42-induced learning and memory impairment was evaluated by Y-maze, passive avoidance, and Morris water maze tests. The results indicated improving cognitive function in the CBL group. After the behavioral tests, antioxidant effects were detected by superoxide dismutase (SOD), oxidized glutathione (GSH)/total GSH, and malondialdehyde (MDA) assays, and inhibition against AChE was also presented in the brain. Finally, oxo-dihydroxy-octadecenoic acid (oxo-DHODE) and trihydroxy-octadecenoic acid (THODE) as main compounds were identified by quadrupole time-of-flight ultraperformance liquid chromatography (Q-TOF UPLC-MS) analysis. Therefore, our studies suggest that CBL could be used as a natural resource for ameliorating Aβ1-42-induced learning and memory impairment.

  8. A disulfide-linked amyloid-beta peptide dimer forms a protofibril-like oligomer through a distinct pathway from amyloid fibril formation.

    Science.gov (United States)

    Yamaguchi, Takahiro; Yagi, Hisashi; Goto, Yuji; Matsuzaki, Katsumi; Hoshino, Masaru

    2010-08-24

    The conversion of the soluble, nontoxic amyloid-beta (Abeta) peptide into an aggregated, toxic form rich in beta-sheets is considered a key step in the development of Alzheimer's disease. Whereas growing evidence indicates that the Abeta amyloid fibrils consist of in-register parallel beta-sheets, little is known about the structure of soluble oligomeric intermediates because of their transient nature. To understand the mechanism by which amyloid fibrils form, especially the initial development of the "nucleus" oligomeric intermediates, we prepared covalently linked dimeric Abeta peptides and analyzed the kinetics of the fibril-forming process. A covalent bond introduced between two Abeta molecules dramatically facilitated the spontaneous formation of aggregates with a beta-sheet structure and affinity for thioflavin T. Transmission electron microscopy revealed, however, that these aggregates differed in morphology from amyloid fibrils, more closely resembling protofibrils. The protofibril-like aggregates were not the most thermodynamically stable state but were a kinetically trapped state. The results emphasize the importance of the conformational flexibility of the Abeta molecule and a balance in the association and dissociation rate for the formation of rigid amyloid fibrils.

  9. Cerebrospinal Fluid Amyloid Beta and Tau Concentrations Are Not Modulated by 16 Weeks of Moderate- to High-Intensity Physical Exercise in Patients with Alzheimer Disease.

    Science.gov (United States)

    Steen Jensen, Camilla; Portelius, Erik; Siersma, Volkert; Høgh, Peter; Wermuth, Lene; Blennow, Kaj; Zetterberg, Henrik; Waldemar, Gunhild; Gregers Hasselbalch, Steen; Hviid Simonsen, Anja

    2016-01-01

    Physical exercise may have some effect on cognition in patients with Alzheimer disease (AD). However, the underlying biochemical effects are unclear. Animal studies have shown that amyloid beta (Aβ), one of the pathological hallmarks of AD, can be altered with high levels of physical activity. The objective of this study was to elucidate the effect of 16 weeks of moderate- to high-intensity physical exercise on the biomarkers of AD, with special emphasis on the amyloidogenic pathway. From a total of 53 patients with AD participating in the Preserving Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer's Disease: The Effect of Physical Exercise (ADEX) study we analyzed cerebrospinal fluid samples for Aβ species, total tau (t-tau), phosphorylated tau (p-tau) and soluble amyloid precursor protein (sAPP) species. We also assessed the patients for apolipoprotein E ε4 (ApoE ε4) genotype. We found no effect of 16 weeks of physical exercise on the selected biomarkers, and no effect of ApoE ε4 genotype. Our findings suggest that the possible effect of physical exercise on cognition in patients with AD is not due to modulation of Aβ, t-tau, p-tau and sAPP species. © 2016 S. Karger AG, Basel.

  10. Protective effects of components of the Chinese herb grassleaf sweetflag rhizome on PC12 cells incubated with amyloid-beta42

    Directory of Open Access Journals (Sweden)

    Zi-hao Liang

    2015-01-01

    Full Text Available The major ingredients of grassleaf sweetflag rhizome are β-asarone and eugenol, which can cross the blood-brain barrier and protect neurons. This study aimed to observe the neuroprotective effects and mechanisms of β-asarone and eugenol, components of the Chinese herb grassleaf sweetflag rhizome, on PC12 cells. First, PC12 cells were cultured with different concentrations (between 1 × 10 -10 M and 1 × 10 -5 M of β-asarone and eugenol. Survival rates of PC12 cells were not significantly affected. Second, PC12 cells incubated with amyloid-beta42, which reduced cell survival, were cultured under the same conditions (1 × 10 -6 M β-asarone and eugenol. The survival rates of PC12 cells significantly increased, while expression levels of the mRNAs for the pro-apoptotic protein Bax decreased, and those for the anti-apoptotic protein Bcl mRNA increased. In addition, the combination of β-asarone with eugenol achieved better results than either component alone. Our experimental findings indicate that both β-asarone and eugenol protect PC12 cells through inhibiting apoptosis, and that the combination of the two is better than either alone.

  11. Pharmacokinetic Profile of Orally Administered Scyllo-Inositol (Elnd005) in Plasma, Cerebrospinal Fluid and Brain, and Corresponding Effect on Amyloid-Beta in Healthy Subjects.

    Science.gov (United States)

    Liang, Earvin; Garzone, Pamela; Cedarbaum, Jesse M; Koller, Martin; Tran, Thao; Xu, Victor; Ross, Brian; Jhee, Stanford S; Ereshefsky, Larry; Pastrak, Aleksandra; Abushakra, Susan

    2013-04-01

    ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days. Plasma and CSF samples were collected at predetermined time points; ELND005 and amyloid-beta (Aβ) fragments were measured by validated bioanalytical methods. Brain ELND005 levels, estimated by (1) H Magnetic Resonance Spectroscopy (MRS) scans were obtained from gray/white matter voxels at baseline and Day 8. ELND005 was well-tolerated during the study. During the apparent steady state, ELND005 plasma levels rapidly peaked at 39.8 µg/mL and decreased to an average trough concentration of 10.6 µg/mL at the end of the 12-hour dosing regimen. In contrast, CSF drug levels slowly peaked at 13.7 µg/mL and remained near the same level with average trough concentrations of 12.4 µg/mL. At Day 8, Brain ELND005 concentrations increased by 58-76% compared to baseline levels. The CSF concentrations achieved in this study were similar to those associated with efficacy in transgenic models of AD. No changes were detected in plasma and CSF levels of Aβ fragments. © The Author(s) 2013.

  12. The effect of acori graminei rhizoma and extract fractions on spatial memory and hippocampal neurogenesis in amyloid beta 1-42 injected mice.

    Science.gov (United States)

    Ma, Yuxin; Tian, Sumin; Sun, Lingzhi; Yao, Shizhang; Liang, Zihao; Li, Shanshan; Liu, Jing; Zang, Linquan; Li, Guoying

    2015-01-01

    Acori graminei Rhizoma (AGR), the dry rhizoma of Acorus gramineus Soland (Araceae), has been used as an Asian traditional herbal medicine against senile dementia, stroke, and cardiovascular disease. Previous studies have revealed neuroprotective effects of AGR on neuronal damage and learning impairment, while mostly focused on the effect of volatile oil fraction of AGR. This study aimed to investigate the neuroprotective effects of different extract fractions from AGR against Alzheimer disease-like symptoms induced by Amyloid Beta (Aß) 1-42 intra-hippocampal injection. On day 7 after intra-hippocampal injection of saline or Aβ1-42, spatial memory was assessed by the first Morris water maze, followed by 3-week intra-gastric administration of saline or water extract, volatile oil fraction, or defatted decoction fraction of AGR respectively. Mice were subsequently subjected to the second Morris water maze task. Levels of Aβ1-42 and expressions of doublecortin and nestin in the hippocampus were examined using immunohistochemistry. Our results suggested that treatment with these different extract fractions from AGR could ameliorate cognitive impairment and down-regulate expressions of doublecortin and nestin in the hippocampus of Aβ1-42 injected mice, in which water extract and volatile oil fractions were more effective in spatial memory than defatted decoction fraction.

  13. Hippocampal Mutant APP and Amyloid Beta Induced Cognitive Decline, Dendritic Spine Loss, Defective Autophagy, Mitophagy and Mitochondrial Abnormalities in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Manczak, Maria; Kandimalla, Ramesh; Yin, Xiangling; Reddy, P Hemachandra

    2018-02-01

    The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in 12-month-old APP transgenic mice. Using rotarod and Morris Water Maze tests, immunoblotting & immunofluorescence, Golgi-cox staining and transmission electron microscopy, we assessed cognitive behavior, protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and quantified dendritic spines and mitochondrial number and length in 12-month-old APP mice that express swedish mutation. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Morris Water Maze and rotarod tests revealed that hippocampal learning and memory and motor learning & coordination were impaired in APP mice relative to wild-type (WT) mice. Increased levels of mitochondrial fission proteins, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), Mitophagy (PINK1 & TERT), synaptic (synaptophysin & PSD95) and dendritic (MAP2) proteins were found in 12-month-old APP mice relative to age-matched non-transgenic WT mice. Golgi-cox staining analysis revealed that dendritic spines are significantly reduced. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice. These findings suggest that hippocampal accumulation of mutant APP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and hippocampal based learning and memory impairments, and mitochondrial structural and functional changes in 12-month-old APP mice. © The Author 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. The Na+/K+-ATPase and the amyloid-beta peptide aβ1-40 control the cellular distribution, abundance and activity of TRPC6 channels.

    Science.gov (United States)

    Chauvet, Sylvain; Boonen, Marielle; Chevallet, Mireille; Jarvis, Louis; Abebe, Addis; Benharouga, Mohamed; Faller, Peter; Jadot, Michel; Bouron, Alexandre

    2015-11-01

    The Na(+)/K(+)-ATPase interacts with the non-selective cation channels TRPC6 but the functional consequences of this association are unknown. Experiments performed with HEK cells over-expressing TRPC6 channels showed that inhibiting the activity of the Na(+)/K(+)-ATPase with ouabain reduced the amount of TRPC6 proteins and depressed Ca(2+) entry through TRPC6. This effect, not mimicked by membrane depolarization with KCl, was abolished by sucrose and bafilomycin-A, and was partially sensitive to the intracellular Ca(2+) chelator BAPTA/AM. Biotinylation and subcellular fractionation experiments showed that ouabain caused a multifaceted redistribution of TRPC6 to the plasma membrane and to an endo/lysosomal compartment where they were degraded. The amyloid beta peptide Aβ(1-40), another inhibitor of the Na(+)/K(+)-ATPase, but not the shorter peptide Aβ1-16, reduced TRPC6 protein levels and depressed TRPC6-mediated responses. In cortical neurons from embryonic mice, ouabain, veratridine (an opener of voltage-gated Na(+) channel), and Aβ(1-40) reduced TRPC6-mediated Ca(2+) responses whereas Aβ(1-16) was ineffective. Furthermore, when Aβ(1-40) was co-added together with zinc acetate it could no longer control TRPC6 activity. Altogether, this work shows the existence of a functional coupling between the Na(+)/K(+)-ATPase and TRPC6. It also suggests that the abundance, distribution and activity of TRPC6 can be regulated by cardiotonic steroids like ouabain and the naturally occurring peptide Aβ(1-40) which underlines the pathophysiological significance of these processes. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Protective effect of systemic L-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25-35) in rat hippocampus.

    Science.gov (United States)

    Carrillo-Mora, Paul; Méndez-Cuesta, Luis A; Pérez-De La Cruz, Verónica; Fortoul-van Der Goes, Teresa I; Santamaría, Abel

    2010-07-11

    Amyloid beta (Abeta) peptide exerts different toxic effects at a cellular level, including over-activation of N-methyl-D-aspartate receptor (NMDAr) and excitotoxicity, synaptic dysfunction and neuronal death. Kynurenic acid (KYNA) is an endogenous antagonist of NMDAr and alpha7 nicotinic receptors. Systemic administrations of both the immediate metabolic precursor of KYNA, L-kynurenine (L-KYN), and a proved inhibitor of KYNA's brain transport, probenecid (PROB), have shown to produce neuroprotective effects in a considerable number of experimental toxic conditions; however, this strategy has not been tested in the toxic model Abeta peptide so far. In this study we evaluated the effects of systemic administration of PROB (50 mg/kg/day for 7 days), L-KYN (75 mg/kg/day for 7 days) and their combination, on behavioural (locomotor activity and spatial memory) and morphological alterations induced by an intrahippocampal infusion of Abeta 25-35 to rats. An additional group was administered with the potent NMDAr antagonist dizocilpine (MK-801, 0.8 mg/kg/day for 7 days) for comparative purposes. A significant improvement of spatial memory was evident in Abeta-lesioned rats since post-lesion day 21 with all treatments tested and this effect was correlated with a reduction of cell damage and a decrease in reactive gliosis in hippocampal CA1 area. Neither L-KYN, nor PROB, or their combination, produced major alterations in motor function when given alone to rats. These results suggest that modulation of NMDAr activity by mean of therapeutic strategies designed to enhance KYNA in the brain may help to counteract neurodegenerative events coursing with Abeta toxicity and excitotoxic patterns. Copyright 2010 Elsevier B.V. All rights reserved.

  16. Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

    Science.gov (United States)

    Schreiner, Simon J.; Liu, Xinyang; Gietl, Anton F.; Wyss, Michael; Steininger, Stefanie C.; Gruber, Esmeralda; Treyer, Valerie; Meier, Irene B.; Kälin, Andrea M.; Leh, Sandra E.; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

    2014-01-01

    Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative

  17. Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Xueli; Tian, Yanli; Li, Zeng; Tian, Xiaoyu; Sun, Hongbin; Liu, Hong; Moore, Anna; Ran, Chongzhao

    2013-11-06

    In this article, we first designed and synthesized curcumin-based near-infrared (NIR) fluorescence imaging probes for detecting both soluble and insoluble amyloid beta (Aβ) species and then an inhibitor that could attenuate cross-linking of Aβ induced by copper. According to our previous results and the possible structural stereohindrance compatibility of the Aβ peptide and the hydrophobic/hydrophilic property of the Aβ13-20 (HHQKLVFF) fragment, NIR imaging probe CRANAD-58 was designed and synthesized. As expected CRANAD-58 showed significant fluorescence property changes upon mixing with both soluble and insoluble Aβ species in vitro. In vivo NIR imaging revealed that CRANAD-58 was capable of differentiating transgenic and wild-type mice as young as 4 months old, the age that lacks apparently visible Aβ plaques and Aβ is likely in its soluble forms. According to our limited studies on the interaction mechanism between CRANAD-58 and Aβ, we also designed CRANAD-17 to attenuate the cross-linking of Aβ42 induced by copper. It is well-known that the coordination of copper with imidazoles on Histidine-13 and 14 (H13, H14) of Aβ peptides could initialize covalent cross-linking of Aβ. In CRANAD-17, a curcumin scaffold was used as an anchoring moiety to usher the designed compound to the vicinity of H13 and H14 of Aβ, and imidazole rings were incorporated to compete with H13/H14 for copper binding. The results of SDS-PAGE gel and Western blot indicated that CRANAD-17 was capable of inhibiting Aβ42 cross-linking induced by copper. This raises a potential for CRANAD-17 to be considered for AD therapy.

  18. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Science.gov (United States)

    Meng, Jia; Li, Yan; Camarillo, Cynthia; Yao, Yue; Zhang, Yina; Xu, Chun; Jiang, Lihong

    2014-01-01

    With the trend of an increasing aged population worldwide, Alzheimer's disease (AD), an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC) inhibitor, suberoylanilidehydroxamic acid (SAHA), may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  19. The anti-tumor histone deacetylase inhibitor SAHA and the natural flavonoid curcumin exhibit synergistic neuroprotection against amyloid-beta toxicity.

    Directory of Open Access Journals (Sweden)

    Jia Meng

    Full Text Available With the trend of an increasing aged population worldwide, Alzheimer's disease (AD, an age-related neurodegenerative disorder, as one of the major causes of dementia in elderly people is of growing concern. Despite the many hard efforts attempted during the past several decades in trying to elucidate the pathological mechanisms underlying AD and putting forward potential therapeutic strategies, there is still a lack of effective treatments for AD. The efficacy of many potential therapeutic drugs for AD is of main concern in clinical practice. For example, large bodies of evidence show that the anti-tumor histone deacetylase (HDAC inhibitor, suberoylanilidehydroxamic acid (SAHA, may be of benefit for the treatment of AD; however, its extensive inhibition of HDACs makes it a poor therapeutic. Moreover, the natural flavonoid, curcumin, may also have a potential therapeutic benefit against AD; however, it is plagued by low bioavailability. Therefore, the integrative effects of SAHA and curcumin were investigated as a protection against amyloid-beta neurotoxicity in vitro. We hypothesized that at low doses their synergistic effect would improve therapeutic selectivity, based on experiments that showed that at low concentrations SAHA and curcumin could provide comprehensive protection against Aβ25-35-induced neuronal damage in PC12 cells, strongly implying potent synergism. Furthermore, network analysis suggested that the possible mechanism underlying their synergistic action might be derived from restoration of the damaged functional link between Akt and the CBP/p300 pathway, which plays a crucial role in the pathological development of AD. Thus, our findings provided a feasible avenue for the application of a synergistic drug combination, SAHA and curcumin, in the treatment of AD.

  20. Blood amyloid beta levels in healthy, mild cognitive impairment and Alzheimer's disease individuals: replication of diastolic blood pressure correlations and analysis of critical covariates.

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    Agustín Ruiz

    Full Text Available Plasma amyloid beta (Aβ levels are being investigated as potential biomarkers for Alzheimer's disease. In AB128 cross-sectional study, a number of medical relevant correlates of blood Aβ40 or Aβ42 were analyzed in 140 subjects (51 Alzheimer's disease patients, 53 healthy controls and 36 individuals diagnosed with mild cognitive impairment. We determined the association between multiple variables with Aβ40 and Aβ42 levels measured in three different blood compartments called i Aβ directly accessible (DA in the plasma, ii Aβ recovered from the plasma matrix (RP after diluting the plasma sample in a formulated buffer, and iii associated with the remaining cellular pellet (CP. We confirmed that diastolic blood pressure (DBP is consistently correlated with blood DA Aβ40 levels (r=-0.19, P=0.032. These results were consistent in the three phenotypic groups studied. Importantly, the observation resisted covariation with age, gender or creatinine levels. Observed effect size and direction of Aβ40 levels/DBP correlation are in accordance with previous reports. Of note, DA Aβ40 and the RP Aβ40 were also strongly associated with creatinine levels (r=0.599, P<<0.001 and to a lesser extent to urea, age, hematocrit, uric acid and homocysteine (p<0.001. DBP and the rest of statistical significant correlates identified should be considered as potential confounder factors in studies investigating blood Aβ levels as potential AD biomarker. Remarkably, the factors affecting Aβ levels in plasma (DA, RP and blood cell compartments (CP seem completely different.

  1. Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.

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    Zhang, Liang; Trushin, Sergey; Christensen, Trace A; Tripathi, Utkarsh; Hong, Courtney; Geroux, Rachel E; Howell, Kyle G; Poduslo, Joseph F; Trushina, Eugenia

    2018-02-26

    Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer's Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype. Copyright © 2018 The Authors. Published by

  2. Tuning the stereo-hindrance of a curcumin scaffold for the selective imaging of the soluble forms of amyloid beta species.

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    Li, Yuyan; Yang, Jian; Liu, Hongwu; Yang, Jing; Du, Lei; Feng, Haiwei; Tian, Yanli; Cao, Jianqin; Ran, Chongzhao

    2017-11-01

    Amyloid peptides and proteins are associated with the pathologies of numerous diseases. In the progression of a disease, amyloids exist in soluble and insoluble forms, which are the dominant species at different stages of the disease and they have different degrees of toxicity. However, differentiating between the soluble and insoluble forms is very challenging with small molecule probes due to multiple obstacles that need to be overcome. Inspired by the recognition principle of antibodies for sAβ, we hypothesized that the accessibility/tightness of soluble and insoluble amyloids could be utilized to design imaging probes to recognize different amyloid forms and the stereo-hindrance tuning strategy could be used to design imaging probes for selectively detecting the soluble amyloid beta (sAβ) species in Alzheimer's disease (AD). Herein, we demonstrated that tuning the stereo-hindrance of the phenoxy-alkyl chains at the 4-position of a curcumin scaffold could lead to certain selectivity for sAβ over insoluble Aβs (insAβ). Among the designed compounds, CRANAD-102 showed a 68-fold higher affinity for sAβ than for insAβ (7.5 ± 10 nM vs. 505.9 ± 275.9 nM). Moreover, our imaging data indicated that CRANAD-102 was indeed capable of detecting sAβ in vivo using 4 month old APP/PS1 mice, in which sAβ is the predominant species in the brain. In addition, we also demonstrated that CRANAD-102 could be used to monitor the increase in sAβ loading from the ages of 4 months old to 12 months old. We believe that CRANAD-102 can be a useful probe for selectively detecting sAβ species in AD and that our probe designing strategy can be applied to other amyloids and will have tremendous impact on AD drug development and other amyloid research.

  3. Rational design of amyloid beta peptide-binding proteins: pseudo-Abeta beta-sheet surface presented in green fluorescent protein binds tightly and preferentially to structured Abeta.

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    Takahashi, Tsuyoshi; Ohta, Kenichi; Mihara, Hisakazu

    2010-02-01

    Some neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease are caused by protein misfolding. In AD, amyloid beta-peptide (Abeta) is thought to be a toxic agent by self-assembling into a variety of aggregates involving soluble oligomeric intermediates and amyloid fibrils. Here, we have designed several green fluorescent protein (GFP) variants that contain pseudo-Abeta beta-sheet surfaces and evaluated their abilities to bind to Abeta and inhibit Abeta oligomerization. Two GFP variants P13H and AP93Q bound tightly to Abeta, K(d) = 260 nM and K(d) = 420 nM, respectively. Moreover, P13H and AP93Q were capable of efficiently suppressing the generation of toxic Abeta oligomers as shown by a cell viability assay. By combining the P13H and AP93Q mutations, a super variant SFAB4 comprising four strands of Abeta-derived sequences was designed and bound more tightly to Abeta (K(d) = 100 nM) than those having only two pseudo-Abeta strands. The SFAB4 protein preferentially recognized the soluble oligomeric intermediates of Abeta more than both unstructured monomer and mature amyloid fibrils. Thus, the design strategy for embedding pseudo-Abeta beta-sheet structures onto a protein surface arranged in the beta-barrel structure is useful to construct molecules capable of binding tightly to Abeta and inhibiting its aggregation. This strategy may provide implication for the diagnostic and therapeutic development in the treatment of AD. (c) 2009 Wiley-Liss, Inc.

  4. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

    Directory of Open Access Journals (Sweden)

    Nicholas J Izzo

    Full Text Available Amyloid beta (Abeta 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD. We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1 protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological

  5. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity.

    Science.gov (United States)

    Izzo, Nicholas J; Xu, Jinbin; Zeng, Chenbo; Kirk, Molly J; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Cruchaga, Carlos; Goate, Alison; Cahill, Michael A; Arancio, Ottavio; Mach, Robert H; Craven, Rolf; Head, Elizabeth; LeVine, Harry; Spires-Jones, Tara L; Catalano, Susan M

    2014-01-01

    Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of

  6. [18F]Flutemetamol amyloid-beta PET imaging compared with [11C]PIB across the spectrum of Alzheimer's disease.

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    Hatashita, Shizuo; Yamasaki, Hidetomo; Suzuki, Yutaka; Tanaka, Kumiko; Wakebe, Daichi; Hayakawa, Hideki

    2014-02-01

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the (18)F-labeled Pittsburgh compound B (PIB) derivative [(18)F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [(18)F]FMM and [(11)C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [(18)F]FMM PET 85 min after injection, 60-min dynamic [(11)C]PIB PET, and cognitive testing. [(18)F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [(18)F]FMM scans had a sensitivity of 97.2% and specificity of 85.3% in distinguishing AD patients from older HC subjects, and a specificity of 100% for young and transitional HC subjects. The [(11)C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p PIB DVR (r = 0.94, n = 145, p PIB PET.

  7. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract.

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    Brewer, Gregory J; Torricelli, John R; Lindsey, Amanda L; Kunz, Elizabeth Z; Neuman, A; Fisher, Derek R; Joseph, James A

    2010-10-01

    Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca(2+) dysregulation was reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS signaling through MAP kinase and cyclic-AMP response element binding protein (CREB), pathways known to be activated in response to amyloid-beta (Aβ). Primary hippocampal neurons were isolated and cultured from embryonic, middle-age or old-age (24 months) rats. Blueberry extract was found to be equally neuroprotective against Aβ neurotoxicity at all ages. Increases in Aβ toxicity with age were associated with age-related increases in immunoreactivity of neurons to pERK and an age-independent increase in pCREB. Treatment with blueberry extract strongly inhibited these increases in parallel with neuroprotection. Simultaneous labeling for ROS and for glutathione with dichlorofluorescein and monochlorobimane showed a mechanism of action of blueberry extract to involve transient ROS generation with an increase in the redox buffer glutathione. We conclude that the increased age-related susceptibility of old-age neurons to Aβ toxicity may be due to higher levels of activation of pERK and pCREB pathways that can be protected by blueberry extract through inhibition of both these pathways through an ROS stress response. These results suggest that the beneficial effects of blueberry extract may involve transient stress signaling and ROS protection that may translate into improved cognition in aging rats and APP/PS1 mice given blueberry extract. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Regional Fluid-Attenuated Inversion Recovery (FLAIR at 7 Tesla correlates with Amyloid beta in Hippocampus and Brainstem of cognitively normal elderly subjects.

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    Simon J Schreiner

    2014-09-01

    Full Text Available Background: Accumulation of amyloid beta (Aβ may occur during healthy aging and is a risk factor for Alzheimer Disease (AD. While individual Aβ-accumulation can be measured non-invasively using Pittsburgh compound-B positron-emission-tomography (PiB-PET, Fluid-Attenuated Inversion Recovery (FLAIR is a Magnetic Resonance Imaging (MRI sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR- intensity. Methods: 14 healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T. Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho, followed by Holm-Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right:rho=0.86; left:rho=0.84, Brainstem (rho=0.85 and left Basal Ganglia vessel region (rho=0.82. Conclusions: Our finding of a significant relationship between PiB- and FLAIR-intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative

  9. Effect of stent-assisted angioplasty on cognitive status and serum levels of amyloid beta in patients with intracranial and/or extracranial artery stenosis

    Directory of Open Access Journals (Sweden)

    Zhao L

    2015-02-01

    Full Text Available Liandong Zhao,1 Ying Zhao,1 Haijun Zhang2 1Department of Neurology, The Second People’s Hospital of Huai’an and The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, 2Department of Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People’s Republic of China Aim: The study reported here aimed to examine how stent-assisted angioplasty affects cognitive status and serum levels of amyloid betas (Aβs 1-40 and 1-42 in patients with cerebral arterial stenosis.Methods: Patients with cerebral arterial stenosis were given stent-assisted angioplasty plus conventional treatment (stent-assisted angioplasty group or conventional treatment alone (control group. Cognitive status and Aβ1-40 and Aβ1-42 serum levels were determined before treatment and at 4 and 8 weeks after treatment.Results: At 4 weeks after treatment, cognitive status in patients with stent-assisted angioplasty had clearly improved. Aβ1-42 serum levels changed insignificantly in all patients. However, Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio decreased further in patients with stent-assisted angioplasty than in patients who received conventional treatment (controls. Eight weeks after treatment, cognitive status in patients who had undergone stent-assisted angioplasty were continuing to improve, Aβ1-42 serum levels had begun to increase dramatically, and Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio had declined further.Conclusion: Stent-assisted angioplasty could improve cognitive status and decrease Aβ1-40 serum levels and Aβ1-40/Aβ1-42 ratio. Keywords: arterial stenosis, Alzheimer’s disease, Aβ1-40, Aβ1-42, Aβ1-40/Aβ1-42 ratio

  10. In Vitro Restoration of an Amyloid-Beta Altered Network Circuitry in a 'Mutated Biomimetic Acetylcholinesterase' Memristor/Memcapacitor Neural Prosthesis

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    John THORNTON

    2015-08-01

    Full Text Available Many diseases involve the ysregulation of acetylcholinesterase (ACHE causing inappropriate production of the neurotransmitter acetylcholine (ACH. Study of how the ACH actually restores a life threatening neural circuitry damage will provide valuable information for study Alzhermer’s disease. An artificial neuronal device was developed with nanostructured biomimetic mutated ACHE gorge membrane on gold chips having memristor/memcapacitor’s characteristics, served as a model for damaged brain circuitry prosthesis, compared before and after ACH treatments, for in vitro evaluation of the memory restoration in the presence of Amyloid-beta (Ab under the conditions of free from tracers and antibodies in NIST human serum. The results are presented in three categories in “Energy-Sensory” images. Before ACH treatments, images showed four stages of circuitry damages from non symptomatic to life threatening. After a 15 nM ACH treatment, the circuitry was restored due to the ACH removed Pathological High Frequency Oscillation (pHFO center during Slow- Waving Sleeping (SWS. After the prosthesis increased hydrophobicity, the High Frequency Oscillation (HFO was created. Results were compared between the recovered and the “normal brain”: 0.14 vs. 0.47 pJ/bit/µm3 for long-term and 14.0 vs.7.0 aJ/bit/µm3 for short-term memory restoration, respectively. The ratio of Rmax/Rmin value is 6.3-fold higher after the treatment of ACH compared without the treatment in the presence of Ab and the reentry sensitivity increased by 613.8- fold.

  11. Xanthene food dye, as a modulator of Alzheimer's disease amyloid-beta peptide aggregation and the associated impaired neuronal cell function.

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    H Edward Wong

    Full Text Available Alzheimer's disease (AD is the most common form of dementia. AD is a degenerative brain disorder that causes problems with memory, thinking and behavior. It has been suggested that aggregation of amyloid-beta peptide (Aβ is closely linked to the development of AD pathology. In the search for safe, effective modulators, we evaluated the modulating capabilities of erythrosine B (ER, a Food and Drug Administration (FDA-approved red food dye, on Aβ aggregation and Aβ-associated impaired neuronal cell function.In order to evaluate the modulating ability of ER on Aβ aggregation, we employed transmission electron microscopy (TEM, thioflavin T (ThT fluorescence assay, and immunoassays using Aβ-specific antibodies. TEM images and ThT fluorescence of Aβ samples indicate that protofibrils are predominantly generated and persist for at least 3 days. The average length of the ER-induced protofibrils is inversely proportional to the concentration of ER above the stoichiometric concentration of Aβ monomers. Immunoassay results using Aβ-specific antibodies suggest that ER binds to the N-terminus of Aβ and inhibits amyloid fibril formation. In order to evaluate Aβ-associated toxicity we determined the reducing activity of SH-SY5Y neuroblastoma cells treated with Aβ aggregates formed in the absence or in the presence of ER. As the concentration of ER increased above the stoichiometric concentration of Aβ, cellular reducing activity increased and Aβ-associated reducing activity loss was negligible at 500 µM ER.Our findings show that ER is a novel modulator of Aβ aggregation and reduces Aβ-associated impaired cell function. Our findings also suggest that xanthene dye can be a new type of small molecule modulator of Aβ aggregation. With demonstrated safety profiles and blood-brain permeability, ER represents a particularly attractive aggregation modulator for amyloidogenic proteins associated with neurodegenerative diseases.

  12. Viewing ageing eyes: diverse sites of amyloid Beta accumulation in the ageing mouse retina and the up-regulation of macrophages.

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    Jaimie Hoh Kam

    Full Text Available BACKGROUND: Amyloid beta (Aβ accumulates in the ageing central nervous system and is associated with a number of age-related diseases, including age-related macular degeneration (AMD in the eye. AMD is characterised by accumulation of extracellular deposits called drusen in which Aβ is a key constituent. Aβ activates the complement cascade and its deposition is associated with activated macrophages. So far, little is known about the quantitative measurements of Aβ accumulation and definitions of its relative sites of ocular deposition in the normal ageing mouse. METHODOLOGY/PRINCIPAL FINDINGS: We have traced Aβ accumulation quantitatively in the ageing mouse retina using immunohistochemistry and Western blot analysis. We reveal that it is not only deposited at Bruch's membrane and along blood vessels, but unexpectedly, it also coats photoreceptor outer segments. While Aβ is present at all sites of deposition from 3 months of age, it increases markedly from 6 months onward. Progressive accumulation of deposits on outer segments was confirmed with scanning electron microscopy, revealing age-related changes in their morphology. Such progress of accumulation of Aβ on photoreceptor outer segments with age was also confirmed in human retinae using immunohistochemistry. We also chart the macrophage response to increases in Aβ showing up-regulation in their numbers using both confocal laser imaging of the eye in vivo followed by in vitro immunostaining. With age macrophages become bloated with cellular debris including Aβ, however, their increasing numbers fail to stop Aβ accumulation. CONCLUSIONS: Increasing Aβ deposition in blood vessels and Bruch's membrane will impact upon retinal perfusion and clearance of cellular waste products from the outer retina, a region of very high metabolic activity. This accumulation of Aβ may contribute to the 30% reduction of photoreceptors found throughout life and the shortening of those that remain. The

  13. Yeast red pigment modifies Amyloid beta growth in Alzheimer disease models in both Saccharomyces cerevisiae and Drosophila melanogaster.

    Science.gov (United States)

    Nevzglyadova, Olga V; Mikhailova, Ekaterina V; Amen, Triana R; Zenin, Valeriy V; Artemov, Alexey V; Kostyleva, Elena I; Mezhenskaya, Daria A; Rodin, Dmitry I; Saifitdinova, Alsu F; Khodorkovskii, Mikhail A; Sarantseva, Svetlana V; Soidla, Tonu R

    2015-01-01

    The effect of yeast red pigment on amyloid-β (Aβ) aggregation and fibril growth was studied in yeasts, fruit flies and in vitro. Yeast strains accumulating red pigment (red strains) contained less amyloid and had better survival rates compared to isogenic strains without red pigment accumulation (white strains). Confocal and fluorescent microscopy was used to visualise fluorescent Aβ-GFP aggregates. Yeast cells containing less red pigment had more Aβ-GFP aggregates despite the lower level of overall GFP fluorescence. Western blot analysis with anti-GFP, anti-Aβ and A11 antibodies also revealed that red cells contained a considerably lower amount of Aβ GFP aggregates as compared to white cells. Similar results were obtained with exogenous red pigment that was able to penetrate yeast cells. In vitro experiments with thioflavine and TEM showed that red pigment effectively decreased Aβ fibril growth. Transgenic flies expressing Aβ were cultivated on medium containing red and white isogenic yeast strains. Flies cultivated on red strains had a significant decrease in Aβ accumulation levels and brain neurodegeneration. They also demonstrated better memory and learning indexes and higher locomotor ability.

  14. [{sup 18}F]Flutemetamol amyloid-beta PET imaging compared with [{sup 11}C]PIB across the spectrum of Alzheimer's disease

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    Hatashita, Shizuo; Yamasaki, Hidetomo [Shonan-Atsugi Hospital, Neurology, PET Center, Atsugi (Japan); Suzuki, Yutaka; Wakebe, Daichi; Hayakawa, Hideki [Shonan-Atsugi Hospital, Radiology, PET Center, Atsugi (Japan); Tanaka, Kumiko [Shonan-Atsugi Hospital, Pharmacology, PET Center, Atsugi (Japan)

    2014-02-15

    The aim was to identify the amyloid beta (Aβ) deposition by positron emission tomography (PET) imaging with the {sup 18}F-labeled Pittsburgh compound B (PIB) derivative [{sup 18}F]flutemetamol (FMM) across a spectrum of Alzheimer's disease (AD) and to compare Aβ deposition between [{sup 18}F]FMM and [{sup 11}C]PIB PET imaging. The study included 36 patients with AD, 68 subjects with mild cognitive impairment (MCI), 41 older healthy controls (HC) (aged ≥56), 11 young HC (aged ≤45), and 10 transitional HC (aged 46-55). All 166 subjects underwent 30-min static [{sup 18}F]FMM PET 85 min after injection, 60-min dynamic [{sup 11}C]PIB PET, and cognitive testing. [{sup 18}F]FMM scans were assessed visually, and standardized uptake value ratios (SUVR) were defined quantitatively in regions of interest identified on coregistered MRI (cerebellar cortex as a reference region). The PIB distribution volume ratios (DVR) were determined in the same regions. Of 36 AD patients, 35 had positive scans, while 36 of 41 older HC subjects had negative scans. [{sup 18}F]FMM scans had a sensitivity of 97.2 % and specificity of 85.3 % in distinguishing AD patients from older HC subjects, and a specificity of 100 % for young and transitional HC subjects. The [{sup 11}C]PIB scan had the same results. Interreader agreement was excellent (kappa score = 0.81). The cortical FMM SUVR in AD patients was significantly greater than in older HC subjects (1.76 ± 0.23 vs 1.30 ± 0.26, p < 0.01). Of the MCI patients, 68 had a bimodal distribution of SUVR, and 29 of them (42.6 %) had positive scans. Cortical FMM SUVR values were strongly correlated with PIB DVR (r = 0.94, n = 145, p < 0.001). [{sup 18}F]FMM PET imaging detects Aβ deposition in patients along the continuum from normal cognitive status to dementia of AD and discriminates AD patients from HC subjects, similar to [{sup 11}C]PIB PET. (orig.)

  15. Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content.

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    Muñoz, Yorka; Paula-Lima, Andrea C; Núñez, Marco T

    2018-03-01

    The transcription factor STAT3 has a crucial role in the development and maintenance of the nervous system. In this work, we treated astrocytes with oligomers of the amyloid beta peptide (AβOs), which display potent synaptotoxic activity, and studied the effects of mediators released by AβOs-treated astrocytes on the nuclear location of neuronal serine-727-phosphorylated STAT3 (pSerSTAT3). Treatment of mixed neuron-astrocyte cultures with 0.5µMAβOs induced in neurons a significant decrease of nuclear pSerSTAT3, but not of phosphotyrosine-705 STAT3, the other form of STAT3 phosphorylation. This decrease did not occur in astrocyte-poor neuronal cultures revealing a pivotal role for astrocytes in this response. To test if mediators released by astrocytes in response to AβOs induce pSerSTAT3 nuclear depletion, we used conditioned medium derived from AβOs-treated astrocyte cultures. Treatment of astrocyte-poor neuronal cultures with this medium caused pSerSTAT3 nuclear depletion but did not modify overall STAT3 levels. Extracellular catalase prevented the pSerSTAT3 nuclear depletion caused by astrocyte-conditioned medium, indicating that reactive oxygen species (ROS) mediate this response. This conditioned medium also increased neuronal oxidative tone, leading to a ryanodine-sensitive intracellular calcium signal that proved to be essential for pSerSTAT3 nuclear depletion. In addition, this depletion decreased BCL2 and Survivin transcription and significantly increased BAX/BCL2 ratio. This is the first description that ROS generated by AβOs-treated astrocytes and neuronal calcium signals jointly regulate pSerSTAT3 nuclear distribution in neurons. We propose that astrocytes release ROS in response to AβOs, which by increasing neuronal oxidative tone, generate calcium signals that cause pSerSTAT3 nuclear depletion and loss of STAT3 protective transcriptional activity. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Evaluation of the Expression of Amyloid Precursor Protein and the Ratio of Secreted Amyloid Beta 42 to Amyloid Beta 40 in SH-SY5Y Cells Stably Transfected with Wild-Type, Single-Mutant and Double-Mutant Forms of the APP Gene for the Study of Alzheimer's Disease Pathology.

    Science.gov (United States)

    Pahrudin Arrozi, Aslina; Shukri, Siti Nur Syazwani; Wan Ngah, Wan Zurinah; Mohd Yusof, Yasmin Anum; Ahmad Damanhuri, Mohd Hanafi; Makpol, Suzana

    2017-11-01

    Neuroblastoma cell lines such as SH-SY5Y are the most frequently utilized models in neurodegenerative research, and their use has advanced the understanding of the pathology of neurodegeneration over the past few decades. In Alzheimer's disease (AD), several pathogenic mutations have been described, all of which cause elevated levels of pathological hallmarks such as amyloid-beta (Aβ). Although the genetics of Alzheimer's disease is well known, familial AD only accounts for a small number of cases in the population, with the rest being sporadic AD, which contains no known mutations. Currently, most of the in vitro models used to study AD pathogenesis only examine the level of Aβ42 as a confirmation of successful model generation and only perform comparisons between wild-type APP and single mutants of the APP gene. Recent findings have shown that the Aβ42/40 ratio in cerebrospinal fluid (CSF) is a better diagnostic indicator for AD patients than is Aβ42 alone and that more extensive Aβ formation, such as accumulation of intraneuronal Aβ, Aβ plaques, soluble oligomeric Aβ (oAβ), and insoluble fibrillar Aβ (fAβ) occurs in TgCRND8 mice expressing a double-mutant form (Swedish and Indiana) of APP, later leading to greater progressive impairment of the brain. In this study, we generated SH-SY5Y cells stably transfected separately with wild-type APP, the Swedish mutation of APP, and the Swedish and Indiana mutations of APP and evaluated the APP expression as well as the Aβ42/40 ratio in those cells. The double-mutant form of APP (Swedish/Indiana) expressed markedly high levels of APP protein and showed a high Aβ2/40 ratio compared to wild-type and single-mutant cells.

  17. Valeriana amurensis improves Amyloid-beta 1-42 induced cognitive deficit by enhancing cerebral cholinergic function and protecting the brain neurons from apoptosis in mice.

    Science.gov (United States)

    Wang, Qiuhong; Wang, Changfu; Shu, Zunpeng; Chan, Kelvin; Huang, Shuming; Li, Yan; Xiao, Yang; Wu, Lihua; Kuang, Haixue; Sun, Xiaobo

    2014-04-28

    Valeriana amurensis, a perennial medicinal herb, has been widely used as anxiolytic, antidepressant, antispasmodic, and sedative in traditional Chinese medicines (TCMs). Moreover, it has been used to treat dementia in Mongolia preparations. In our previous study, we reported that AD-effective fraction of Valeriana amurensis (AD-EFV) has protective effect on Aβ-induced toxicity in PC12 cells. Up to now, however, the therapeutic effect of Valeriana amurensis on Alzheimer disease (AD) has not been explored. This study was designed to determine whether the AD-EFV could improve the Amyloid-beta (Aβ)-induced cognitive deficit and to explore the mechanism of AD-EFV improves cognitive deficit in intact animals. The constituents of AD-EFV were isolated with silica gel, octadecyl silica gel (ODS) column chromatography (CC) and preparative HPLC. The structures of compounds were determined by detailed NMR and ESI-MS data analyses. AD mice model was established by injecting A(β1-42) (1 μL, 200 μmol) into the bilateral ventricle. Cognitive performance was evaluated by the Morris water maze (MWM) test. The level of cerebral acetylcholine (ACh), the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were investigated using Enzyme-linked immunoassay (ELISA) kits. Brain sections were processed and neuronal apoptosis in hippocampus were evaluated by Hematoxylin and Eosin (HE), Nissl, and Tunel stainings. The analyses of p-ERK/ERK and Bcl-2/Bax protein expression by western blot assay were used to explore the anti-neuronal apoptosis mechanism of AD-EFV. Seventeen compounds (15 lignans and two iridoids) were isolated from AD-EFV. A significant improvement in cognitive function was observed in administrated AD-EFV AD model mice. AD-EFV increased the ACh level by enhancing the ChAT activity but has no effect on AChE activity in the cerebral cortex and hippocampus in mice. Moreover, the histological injury in hippocampus CA1 induced by A(β1-42) was

  18. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study.

    Science.gov (United States)

    Rinne, Juha O; Brooks, David J; Rossor, Martin N; Fox, Nick C; Bullock, Roger; Klunk, William E; Mathis, Chester A; Blennow, Kaj; Barakos, Jerome; Okello, Aren A; Rodriguez Martinez de Liano, Sofia; Liu, Enchi; Koller, Martin; Gregg, Keith M; Schenk, Dale; Black, Ronald; Grundman, Michael

    2010-04-01

    Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimer's disease. Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to

  19. Memantine and Ketamine Differentially Alter NMDA Receptor Desensitization.

    Science.gov (United States)

    Glasgow, Nathan G; Povysheva, Nadezhda V; Azofeifa, Andrea M; Johnson, Jon W

    2017-10-04

    Memantine and ketamine are clinically useful NMDA receptor (NMDAR) open channel blockers that inhibit NMDARs with similar potency and kinetics, but display vastly different clinical profiles. This discrepancy has been hypothesized to result from inhibition by memantine and ketamine of overlapping but distinct NMDAR subpopulations. For example, memantine but not ketamine may inhibit extrasynaptic NMDARs more effectively than synaptic NMDARs. However, the basis for preferential NMDAR inhibition depending on subcellular location has not been investigated systematically. We integrated recordings from heterologously expressed single NMDAR subtypes, kinetic modeling, and recordings of synaptically evoked NMDAR responses in acute brain slices to investigate mechanisms by which channel blockers may distinguish NMDAR subpopulations. We found that memantine and ketamine differentially alter NMDAR desensitization and that memantine stabilizes a Ca 2+ -dependent desensitized state. As a result, inhibition by memantine of GluN1/2A receptors in tsA201 cells and of native synaptic NMDARs in cortical pyramidal neurons from mice of either sex increased in conditions that enhanced intracellular Ca 2+ accumulation. Therefore, differential inhibition by memantine and ketamine based on NMDAR location is likely to result from location dependence of the intensity and duration of NMDAR activation. Modulation of Ca 2+ -dependent NMDAR desensitization is an unexplored mechanism of inhibitory action with the potential to endow drugs with NMDAR selectivity that leads to superior clinical profiles. Our results suggest that designing compounds to target specific receptor states, rather than specific receptor types, may be a viable strategy for future drug development. SIGNIFICANCE STATEMENT Memantine and ketamine are NMDA receptor (NMDAR) channel-blocking drugs with divergent clinical effects. Understanding mechanistically their differential actions may advance our understanding of nervous

  20. Cerebrospinal fluid levels of amyloid beta 1-43 in patients with amnestic mild cognitive impairment or early Alzheimer’s disease: a 2-year follow-up study

    Directory of Open Access Journals (Sweden)

    Camilla eLauridsen

    2016-03-01

    Full Text Available Abstract IntroductionBiomarkers that will reliably predict the onset of Alzheimer’s disease (AD are urgently needed. Although cerebrospinal fluid (CSF amyloid beta 1-42 (Aβ42, total tau and phosphorylated tau can be used to complement the clinical diagnosis of AD, amnestic mild cognitive impairment (aMCI, the prodromal phase of AD, is heterogeneous. Biomarkers should be able to determine which patients with aMCI are at greatest risk of AD. Histological studies and animal models indicate that amyloid beta 1-43 (Aβ43 aggregates early, and may play a role in the pathological process of AD. We have examined levels of CSF Aβ43 in a two-year longitudinal study of aMCI and early AD. Materials and methodsCSF was collected at baseline, and after one and two years from patients with AD (n=19, and patients with aMCI (n=42. Of these, 21 progressed to AD during the two years of study, whereas 21 did not. Controls (n=32 were lumbar punctured at baseline only. CSF analyses of Aβ43, Aβ42 and total tau were carried out with ELISA.ResultsAt baseline, CSF Aβ43, CSF Aβ42 and ratios with total tau could be used to separate controls from all three patient groups. CSF Aβ43, but not Aβ42, could separate patients with aMCI who progressed to AD during the two years of follow-up, from those that did not. The CSF total tau/Aβ43 ratio had a slightly but significantly larger area under the receiver operating characteristic curve when compared to the CSF total tau/Aβ42 ratio. CSF Aβ43 levels, but not Aβ42 levels, decreased from baseline to two years in the AD group.Discussion and conclusionCSF Aβ43 was demonstrated to be significantly reduced in patients already by the time that aMCI or AD was diagnosed, compared to controls, and this change must have occurred during the preclinical period. Since our results suggested that CSF Aβ43 distinguishes between subgroups of patients with aMCI better than CSF Aβ42, it may prove to be a useful additional biomarker for

  1. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

    Science.gov (United States)

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-12-01

    Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  2. Regional Hippocampal Atrophy and Higher Levels of Plasma Amyloid-Beta Are Associated With Subjective Memory Complaints in Nondemented Elderly Subjects

    DEFF Research Database (Denmark)

    Cantero, Jose L; Iglesias, Juan E.; Van Leemput, Koen

    2016-01-01

    volume differences in hippocampal subregions were further correlated with plasma Aβ levels and with objective memory performance. Results: Individuals with SMC exhibited significantly higher Aβ1-42 concentrations and lower volumes of CA1, CA4, dentate gyrus, and molecular layer compared with SMC......(-) participants. Regression analyses further showed significant associations between lower volume of the dentate gyrus and both poorer memory performance and higher plasma Aβ1-42 levels in SMC(+) participants. Conclusions: The presence of SMC, lower volumes of specific hippocampal regions, and higher plasma Aβ1...

  3. Memantine prevents MDMA-induced neurotoxicity.

    Science.gov (United States)

    Chipana, C; Camarasa, J; Pubill, D; Escubedo, E

    2008-01-01

    MDMA (ecstasy) is an illicit drug causing long-term neurotoxicity. Previous studies demonstrated the interaction of MDMA with alpha-7 nicotinic acetylcholine receptor (nAChR) in mouse brain membranes and the involvement of alpha-7 nicotinic acetylcholine receptors (nAChR) in dopaminergic neurotoxicity induced by MDMA in mice. The aim of the present study was to investigate the utility of memantine (MEM), an alpha-7 nAChR antagonist used for treatment of Alzheimer's disease patients, to prevent neurotoxicity induced by MDMA in rats and the oxidative effect of this amphetamine derivative in mice striatal synaptosomes. In isolated mouse striatal synaptosomes (an in vitro model of MDMA neurotoxicity of dopaminergic origin), MDMA (50 microM)-induced reactive oxygen species (ROS) production that was fully inhibited by MEM (0.3 microM). This effect of MEM was fully prevented by PNU 282987 (0.5 microM), a specific agonist of alpha-7 nAChR. The preventive effect of MEM on this oxidative effect can be attributed to a direct antagonism between MDMA (acting probably as agonist) and MEM (acting as antagonist) at the alpha-7 nAChR. In Dark Agouti rats (an in vivo model of MDMA neurotoxicity of serotonergic origin), a single dose of MDMA (18 mg/kg) induced persistent hyperthermia, which was not affected by MEM pre-treatment. [(3)H]Paroxetine binding (a marker of serotonergic injury) was measured in the hippocampus of animals killed at 24h and 7 days after treatment. MDMA induced a significant reduction in [(3)H]paroxetine binding sites at both times of sacrifice that was fully prevented by pre-treatment with MEM. Since previous studies demonstrate that increased glutamate activity is not involved in the neurotoxic action of MDMA, it can be concluded that the effectiveness of MEM against MDMA-induced neurotoxicity would be the result of blockade of alpha-7 nAChR, although an indirect mechanism based on the interplay among the various neurotransmission systems leading to an

  4. Update on the use of memantine in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Robert J van Marum

    2009-03-01

    Full Text Available Robert J van MarumGeriatric Department, University Medical Center Utrecht, Utrecht, The NetherlandsAbstract: Memantine is a low to moderate affinity N-methyl-D-aspartate receptor (NMDAR antagonist. The effects of memantine in Alzheimer’s disease (AD have been studied in 7 randomized controlled trials in many post-hoc analyses. Three out of four RCTs in patients with moderate to severe AD (Mini Mental State Examination [MMSE] 14 showed a statistically significant but clinically small positive effect of memantine on cognition, global functioning, activities of daily living (ADL and neuropsychiatric symptoms. No effects on these outcome measures could be found in the three RCTs studying patients with mild to moderate AD (MMSE 14–24. Two of these studies evaluated the effect of addition of memantine to donepezil. Only the study in patients with mild to moderate AD showed a positive effect of addition of memantine on cognition, ADL, global functioning and neuropsychiatric functioning. Cost-effectiveness of memantine therapy remains controversial. Post-hoc analyses and observational studies suggest some effects on agitation/aggression, delusions or hallucinations. Side effects of memantine are usually mild and seem to be comparable with placebo. In this review, an oversight of pharmacodynamics and pharmacokinetics of memantine is presented. Also, published data concerning efficacy and safety in patients with AD are presented.Keywords: dementia, Alzheimer’s disease, drug therapy, memantine

  5. Memantine reduces stealing behavior and impulsivity in kleptomania

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N

    2013-01-01

    Kleptomania is characterized by repetitive stealing behavior and has been associated with deleterious unwanted outcomes including forensic contact and increased rates of suicidal behavior. Very few trials have been conducted to investigate pharmacological treatment options for this neglected...... condition. Memantine is an NMDA-receptor antagonist that has shown promising results in the treatment of other behavioral addictions and substance addictions. Twelve individuals with kleptomania received memantine (10 mg/day, titrated to 30 mg/day maximum depending on clinical response and tolerability......) over the course of 8 weeks, in an open-label trial. The effects of treatment were quantified using well-validated measures and select neurocognitive tests (last observation carried forward analyses). Kleptomania disease severity scores decreased across all measures considered, and 11 (91...

  6. Effects of Memantine and Oleocanthal on Alzheimer's Disease

    Science.gov (United States)

    Houston, Mariyam; Bonacum, Jason; Zhang, Guoping

    2014-03-01

    Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by accumulation of neuritic plaques composed of amyloid- β (A β) proteins and neurofibrillary tangles composed of tau proteins. Although there is no known cure for AD, the symptoms can be treated with a drug called memantine. Memantine acts an NMDAR antagonist by inhibiting the action of the NMDA receptor. Recently, Oleocanthal, a phenolic molecule that is found in extra virgin olive oil, has been linked to reduced risk of AD. Though the mechanism by which Oleocanthal plays in reducing the risk of AD is not completely understood, recent studies have shown that Oleocanthal somehow inhibits the formation of the neurofibrillary tangles and reduces the formation of A β senile plaques. Our first-principles calculation, based on Gaussian03 program, shows that in the M2 segment, memantine binds to serine, but ketamine binds to glycine. This may explain their different effects, despite the fact that they are both NMDAR antagonists. Using the same method, we also investigate how Oleocanthal binds to the peptides by comparing the relative energies of each of the structures. Our results may help better understand the mechanism by which Oleocanthal decreases the chances of developing AD. U.S. DOE, DE-FG02-06ER46304; ISU SURE program; University of the CSRC; DEPT of Chemistry and Physics.

  7. Deficiency in either COX-1 or COX-2 genes does not affect amyloid beta protein burden in amyloid precursor protein transgenic mice.

    Science.gov (United States)

    Park, Sun Ah; Chevallier, Nathalie; Tejwani, Karishma; Hung, Mary M; Maruyama, Hiroko; Golde, Todd E; Koo, Edward H

    2016-09-09

    Epidemiologic studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk for developing Alzheimer's disease (AD). Because the primary mode of action of NSAIDs is to inhibit cyclooxygenase (COX) activity, it has been proposed that perturbed activity of COX-1 or COX-2 contributes to AD pathogenesis. To test the role of COX-1 or COX-2 in amyloid deposition and amyloid-associated inflammatory changes, we examined amyloid precursor protein (APP) transgenic mice in the context of either COX-1 or COX-2 deficiency. Our studies showed that loss of either COX-1 or COX-2 gene did not alter amyloid burden in brains of the APP transgenic mice. However, one marker of microglial activation (CD45) was decreased in brains of COX-1 deficient/APP animals and showed a strong trend in reduction in COX-2 deficient/APP animals. These results suggest that COX activity and amyloid deposition in brain are likely independent processes. Further, if NSAIDs do causally reduce the risks of AD, then our findings indicate that the mechanisms are likely not due primarily to their inhibition on COX or γ-secretase modulation activity, the latter reported recently after acute dosing of ibuprofen in humans and nonhuman primates. Copyright © 2016. Published by Elsevier Inc.

  8. Effects of an amyloid-beta 1-42 oligomers antibody screened from a phage display library in APP/PS1 transgenic mice.

    Science.gov (United States)

    Wang, Jianping; Li, Nan; Ma, Jun; Gu, Zhiqiang; Yu, Lie; Fu, Xiaojie; Liu, Xi; Wang, Jian

    2016-03-15

    We screened anti-Aβ1-42 antibodies from a human Alzheimer's disease (AD) specific single chain variable fragment (scFv) phage display library and assessed their effects in APP/PS1 transgenic mice. Reverse transcription-PCR was used to construct the scFv phage display library, and screening identified 11A5 as an anti-Aβ1-42 antibody. We mixed 11A5 and the monoclonal antibody 6E10 with Aβ1-42 and administered the mixture to Sprague-Dawley rats via intracerebroventricular injection. After 30 days, rats injected with the antibody/Aβ1-42 mixture and those injected with Aβ1-42 alone were tested on the Morris water maze. We also injected 11A5 and 6E10 into APP/PS1 transgenic mice and assessed the concentrations of Aβ in brain and peripheral blood by ELISA at 1-month intervals for 3 months. Finally we evaluated behavior changes in the Morris water maze. Rats injected with Aβ1-42 and mixed antibodies showed better performance in the Morris water maze than did rats injected with Aβ1-42 alone. In APP/PS1 transgenic mice, Aβ concentration was lower in the brains of the antibody-treated group than in the control group, but higher in the peripheral blood. The antibody-treated mice also exhibited improved behavioral performance in the Morris water maze. In conclusion, anti-Aβ1-42 antibodies (11A5) screened from the human scFv antibody phage display library promoted the efflux or clearance of Aβ1-42 and effectively decreased the cerebral Aβ burden in an AD mouse model. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Perforin Promotes Amyloid Beta Internalisation in Neurons.

    Science.gov (United States)

    Lana, Erica; Khanbolouki, Mahbod; Degavre, Charline; Samuelsson, Eva-Britt; Åkesson, Elisabet; Winblad, Bengt; Alici, Evren; Lithner, Christina Unger; Behbahani, Homira

    2017-03-01

    Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ 40 and Aβ 42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ 40 (250 nM) compared with Aβ 42 (100 nM). The internalised Aβ 40 showed a dot-like pattern of distribution whereas Aβ 42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ 40 and Aβ 42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ 40 ) and 50 (Aβ 42 ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ 42 , but not Aβ 40 , was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.

  11. Sensitive and rapid HPLC method for determination of memantine in human plasma using OPA derivatization and fluorescence detection: application to pharmacokinetic studies.

    Science.gov (United States)

    Zarghi, Afshin; Shafaati, Alireza; Foroutan, Seyed Mohsen; Khoddam, Arash; Madadian, Babak

    2010-01-01

    A rapid, sensitive and reproducible HPLC method was developed and validated for the analysis of memantine in human plasma after derivatization with o-phthaldialdehyde (OPA) and fluorescence detection. Amantadine was used as internal standard. The derivatized memantine and amantadine were eluted in less than 10 min with no interference from endogenous plasma peaks. The analysis was carried out on a monolithic silica column (Chromolith Performance RP-18e, 100Ã4.6 mm). The mobile phase was composed of a mixture of acetonitrile and 0.025 M phosphate buffer (50:50, v/v, pH=4.6) with a flow rate of 2.5 mLmin(â1). The excitation and emission wavelengths were set at 335 nm and 440 nm respectively. The assay enables the measurement of memantine for therapeutic drug monitoring with a lower quantification limit of 2 ngmL(â1). The method involves simple extraction procedure and analytical recovery was 82.8Â 0.9%. The calibration curve was linear over the concentration range 2â80 ngmL(â1). The coefficients of variation for inter-day and intra-day assay were found to be less than 8%. The method was successfully applied to pharmacokinetic studies in humans.

  12. Progress in mechanisms of acetylcholinesterase inhibitors and memantine for the treatment of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Shao-Min Li

    2015-01-01

    Full Text Available Alzheimer's disease (AD is the most common causes of dementia in the elderly. Currently, only two classes of drugs, acetylcholinesterase inhibitors (AChEIs and memantine are approved. AChEIs ameliorate cognitive and psychiatric symptoms in AD patients through activation of acetylcholine (ACh receptors by increased synaptic ACh levels and also have protective effects against glutamate neurotoxicity and inflammation, whereas memantine appears to mainly protect against excitotoxicity and neurodegeneration. Herein, we review the pharmacologic properties of the available AChEIs and memantine, and focus on recent progress in the mechanisms of AD in relation to acetylcholinergic and glutamatergic involvement.

  13. Effect of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity.

    Science.gov (United States)

    Topdag, M; Iseri, M; Gelenli, E; Yardimoglu, M; Yazir, Y; Ulubil, S A; Topdag, D O; Ustundag, E

    2012-11-01

    This study aimed to contribute to the literature on the prevention and treatment of ototoxicity due to various drugs and chemicals. This study compared the histological effects of intratympanic dexamethasone, memantine and piracetam on cellular apoptosis due to cisplatin ototoxicity, in 36 rats. Dexamethasone and memantine had significant effects on the stria vascularis, organ of Corti and spiral ganglion (p piracetam decreased the apoptosis rate, this effect was not statistically significant (p > 0.05). Dexamethasone and memantine were found superior to piracetam in reducing apoptosis due to cisplatin ototoxicity. Further studies of this subject are needed, incorporating electron microscopy and auditory brainstem response testing.

  14. Combined application of tenuigenin and β-asarone improved the efficacy of memantine in treating moderate-to-severe Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Chang W

    2018-03-01

    Full Text Available Wenguang Chang,1 Junfang Teng2 1Department of Neurology, Xinxiang Central Hospital, Xinxiang, Henan, People’s Republic of China; 2Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Henan, People’s Republic of China Background: Alzheimer’s disease (AD is a slowly progressive neurodegenerative disease which cannot be cured at present. The aim of this study was to assess whether the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD.Patients and methods: One hundred and fifty-two patients with moderate-to-severe AD were recruited and assigned to two groups. Patients in the experiment group received β-asarone 10 mg/d, tenuigenin 10 mg/d, and memantine 5–20 mg/d. Patients in the control group only received memantine 5–20 mg/d. The Mini Mental State Examination (MMSE, Clinical Dementia Rating Scale (CDR, and Activities of Daily Living (ADL were used to assess the therapeutic effects. The drug-related adverse events were used to assess the safety and acceptability. Treatment was continued for 12 weeks.Results: After 12 weeks of treatment, the average MMSE scores, ADL scores, and CDR scores in the two groups were significantly improved. But, compared to the control group, the experimental group had a significantly higher average MMSE score (p<0.00001, lower average ADL score (p=0.00002, and lower average CDR score (p=0.030. Meanwhile, the rates of adverse events were similar between the two groups. Subgroup analysis indicated that the most likely candidates to benefit from this novel method might be the 60–74-years-old male patients with moderate AD.Conclusion: These results demonstrated that the combined application of β-asarone and tenuigenin could improve the efficacy of memantine in treating moderate-to-severe AD. The clinical applicability of this novel method showed greater promise and should be further explored. Keywords

  15. An Open Label Study of Memantine Treatment in Three Subtypes of Frontotemporal Lobar Degeneration

    OpenAIRE

    Boxer, Adam L.; Lipton, Anne M.; Womack, Kyle; Merrilees, Jennifer; Neuhaus, John; Pavlic, Danijela; Gandhi, Anisha; Red, Dana; Kristen-Martin-Cook; Svetlik, Doris; Miller, Bruce L.

    2009-01-01

    There are currently no FDA-approved treatments for frontotemporal lobar degeneration (FTLD). The objectives of this study were to explore the tolerability of memantine treatment in FTLD and to monitor for possible effects on behavior, cognition and function. 43 individuals who met clinical criteria for FTLD (21 with frontotemporal dementia [FTD], 13 with semantic dementia [SD] and 9 with progressive nonfluent aphasia [PA]) received 26 weeks of open label treatment with memantine at a target d...

  16. Differential regulation of GluA1 expression by ketamine and memantine.

    Science.gov (United States)

    Zhang, Ke; Yamaki, Vitor Nagai; Wei, Zhisheng; Zheng, Yu; Cai, Xiang

    2017-01-01

    Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Memantine facilitates memory consolidation and reconsolidation in the day-old chick.

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    Samartgis, Jodi R; Schachte, Leslie; Hazi, Agnes; Crowe, Simon F

    2012-05-01

    Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been approved for the treatment of the cognitive deficits noted in Alzheimer's disease. While there is a body of research that supports memantine's facilitative action upon memory compromise, this series of studies aimed to investigate the effects of this drug in healthy animals with intact memory functioning. A 0.1 mM dose of memantine injected immediately after a weakly aversive training event (i.e. 20% v/v methyl anthranilate) was found to enhance passive avoidance learning for this event in day-old chicks up to 24 h following training. The same dose of memantine was also observed to enhance memory for the training event when it was administered in conjunction with a reminder trial. These results suggest that memantine is capable of facilitating both memory consolidation as well as memory reconsolidation. It was concluded that memantine's mechanism may involve the short-term or intermediate memory phases of the Gibbs and Ng model of memory, and that the current findings represent enhancement of intact memory, rather than amelioration of memory compromise. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  18. Protective Effects of Memantine Induced by Cerebral Ischemia and Reperfusion Injury in Rats

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    Hasan Hüseyin Özdemir

    2013-09-01

    Full Text Available OBJECTIVE: The severity of apoptosis developing after hypoxia-ischemia and reperfusion is an indicator of cerebral injury. In cerebral ischemia, there are many factors initiating the events progressing to cell death. The most common leading cause is excessive increase in intracellular calcium concentration. Ion channels in NMDA receptors cause cell death by increasing Ca+2 entries into the cell. Memantine is non-competitive excitatory amino acid blocker of NMDA receptor. Studies suggesting administration of memantine before and after ischemia decreasing the neural injury have been published. In this study we aimed to examine the memantine could have decreasing effect on neuronal injury resulting with apoptosis especially in penumbra region after ischemia and its effects on antioxidants and oxidants in brain tissues. METHODS: Experimental study was performed in three groups each of them including 7 rats. No procedure was performed in control group and it was used for evaluation of the normal brain tissue. Transient focal cerebral ischemia was performed by clipping the right common carotid arteries of the rats in ischemia and ischemia-drug groups. Ten mg/kg intraperitoneal memantine was administered in ischemia-drug group 30 minutes after ischemia and for 5 days. All of the rats were sacrificed after the experiment. Antioxidant and oxidant levels of the cerebral tissues were measured. Apoptotic cells were determined by immunohistochemically with TUNEL method. RESULTS: When the group administered memantine was compared with ischemia group, it was observed that memantine decreased apoptotic cells in the brain tissue and provided improvement in oxidant levels (p<0.05. CONCLUSION: In conclusion, memantine may be effective in prevention of apopitozis and neuronal injury in cerebral ischemic tissue via decreasing cerebral oxidant formations

  19. Memory and mood during MDMA intoxication, with and without memantine pretreatment.

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    de Sousa Fernandes Perna, E B; Theunissen, E L; Kuypers, K P C; Heckman, P; de la Torre, R; Farre, M; Ramaekers, J G

    2014-12-01

    Previous studies have shown that single doses of MDMA can affect mood and impair memory in humans. The neuropharmacological mechanisms involved in MDMA-induced memory impairment are not clear. Memantine, an NMDA and alpha 7 nicotinic acetylcholine (ACh) receptor antagonist, was able to reverse MDMA-induced memory impairment in rats. This study investigated whether treatment with memantine can prevent MDMA-induced memory impairment in humans. 15 subjects participated in a double-blind, placebo controlled, within-subject design. Subjects received both pre-treatment (placebo/memantine 20 mg) (T1) and treatment (placebo/MDMA 75 mg) (T2) on separate test days. T1 preceded T2 by 120 min. Memory function was assessed 90 min after T2 by means of a Visual Verbal Learning Task, a Prospective Memory Task, the Sternberg Memory Task and the Abstract Visual Pattern Learning Task. Profile of Mood State and psychomotor performance were also assessed to control whether MDMA and memantine interactions would selectively pertain to memory or transfer to other domains as well. MDMA significantly impaired performance in the visual verbal learning task and abstract visual pattern learning task. Pre-treatment with memantine did not prevent MDMA-induced memory impairment in these two tasks. Both positive (vigour, arousal, elation) and negative mood effects (anxiety) were increased by MDMA. The responses were not altered by pretreatment with memantine which had no effect on memory or mood when given alone. These preliminary results suggest that memantine does not reverse MDMA-induced memory impairment and mood in humans. This article is part of the Special Issue entitled 'CNS Stimulants'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Memantine enhances the effect of olanzapine in patients with schizophrenia: A randomized, placebo-controlled study

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    Ahmad Fakhri

    2016-12-01

    Full Text Available Glutamate dysregulation may be involved in the neuropathology of schizophrenia. Memantine, a drug approved by the FDA for the treatment of moderate to severe Alzheimer's disease, acts as a partial uncompetitive NMDA receptor antagonist. The aim of this study was to examine the efficacy of memantine as an adjunctive treatment to olanzapine in patients with schizophrenia. In this double-blind, placebo-controlled studies, patients with schizophrenia according to DSM-IV clinical criteria were selected. Patients were randomly assigned to receive either memantine (week 1:10 mg/day; weeks 2-6:20 mg/day plus olanzapine (15-20 mg/day or olanzapine plus placebo. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. Results showed that memantine significantly improved the positive and negative PANSS score in patients maintained on olanzapine after six weeks compared to olanzapine alone (P<0.001. Furthermore, female patients showed significantly better response than males, especially in positive PANSS score. No significant changes in extrapyramidal symptoms were observed.These findings indicate that olanzapine efficacy might be augmented with memantine. Furthermore, this effect is more remarkable in female patients with schizophrenia.

  1. The cytotoxic effect of memantine and its effect on cytoskeletal proteins expression in metastatic breast cancer cell line

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    Sima Seifabadi

    2017-01-01

    Full Text Available Objective(s:Breast cancer is an important leading cause of death from cancer. Stathmin and tau proteins are regulators of cell motility, and their overexpression is associated with the progression and bad prognosis of breast cancer. Memantine, an N-methyl-D-aspartate (NMDA receptor antagonist, is the potential inhibitor of tau protein in neurons. This study determines the effect of memantine on breast cancer cell migration and proliferation, tau and stathmin gene expression in cancer cells and its synergistic effect with paclitaxel.   Materials and Methods: The cell proliferation was evaluated by MTT assay and for this purpose, MCF-7 breast cancer cells were treated with various concentration of memantine (2, 20 and 100 μg/ml. Tau and stathmin mRNA expression was evaluated through quantitative real time RT-PCR method. The migration of cancer cells treated with memantine for 24 hr was compared to non-treated cells using an in vitro transmembrane migration assay. Results: Incubation of breast cancer cells with memantine resulted in a dose dependent reduction in cell survival (P=0.0001. Paclitaxel (100 nM showed synergistic effect with memantine (P=0.0001. Memantine significantly decreased tau and stathmin mRNA expression (by RT-PCR, so that 100 µmol/l of memantine decreased tau and stathmin expression by 46% (P=0.0341 and 33% (P=0.043, respectively. Migration of cells was also decreased by memantine (P=0.0001. Conclusion: The presented data shows that memantine reduced mRNA levels of tau and stathmin proteins and also reduced cellular migration.

  2. Effects of Memantine, an NMDA Antagonist, on Metabolic Syndromes in Female NMRI Mice

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    Naser Osanloo

    2015-10-01

    Results: The intraperitoneal administration of memantine increased plasma corticosterone, water intake, fecal weight and eating latency, but had no effect on food intake or weight. The dose and site-dependent intra-accumbens administration of memantine either exacerbated the effects of stress on plasma corticosterone levels and water and food intake, or else had no effect on these parameters. Furthermore, the administration of memantine had no effect on animal’s weight and inhibited the effects of stress on fecal weight and eating latency. Discussion: The inhibition of glutamate NMDA receptors in the nucleus accumbens can inhibit and/or exacerbate the dose and site-dependent effects of chronic stress, with gender playing a significant role in producing this effect.

  3. Memantine prevents cardiomyocytes nuclear size reduction in the left ventricle of rats exposed to cold stress

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    Adriano Meneghini

    2009-01-01

    Full Text Available OBJECTIVES: Memantine is an N-methyl-d-aspartate (NMDA glutamate receptor antagonist used to treat Alzheimer's disease. Previous studies have suggested that receptor blockers act as neuroprotective agents; however, no study has specifically investigated the impact that these drugs have on the heart. We sought to evaluate the effects of memantine on nuclear size reduction in cardiac cells exposed to cold stress. METHOD: We used male EPM-Wistar rats (n=40 divided into 4 groups: 1 Matched control (CON; 2 Memantine-treated rats (MEM; 3 Rats undergoing induced hypothermia (IH and 4 Rats undergoing induced hypothermia that were also treated with memantine (IHM. Animals in the MEM and IHM groups were treated by oral gavage administration of 20 mg/kg/day memantine over an eight-day period. Animals in the IH and IHM groups were submitted to 4 hours of hypothermia in a controlled environment with a temperature of - 8ºC on the last day of the study. RESULTS: The MEM group had the largest cardiomyocyte nuclear size (151 ± 3.5 μm³ vs. CON: 142 ± 2.3 μm³; p<0.05, while the IH group had the smallest mean value of nuclear size. The nuclear size of the IHM group was preserved (125 ± 2.9 μm³ compared to the IH group (108 ± 1.7 μm³; p<0.05. CONCLUSION: Memantine prevented the nuclear size reduction of cardiomyocytes in rats exposed to cold stress.

  4. The effect of the NMDA channel blocker memantine on salicylate-induced tinnitus in rats.

    Science.gov (United States)

    Ralli, M; Troiani, D; Podda, M V; Paciello, F; Eramo, S L M; de Corso, E; Salvi, R; Paludetti, G; Fetoni, A R

    2014-06-01

    Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The

  5. Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial.

    Science.gov (United States)

    Yang, Jin-Chen; Rodriguez, Annette; Royston, Ashley; Niu, Yu-Qiong; Avar, Merve; Brill, Ryan; Simon, Christa; Grigsby, Jim; Hagerman, Randi J; Olichney, John M

    2016-02-22

    Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory "oddball" task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection. Analysis also revealed that memantine treatment normalized the P2 habituation effect at the follow-up visit. These findings indicate that memantine may benefit attentional processes that represent fundamental components of executive function/dysfunction, thought to comprise the core cognitive deficit in FXTAS. The results provide evidence of target engagement of memantine, as well as therapeutically relevant information that could further the development of specific cognitive or disease-modifying therapies for FXTAS.

  6. Memantine reduces stealing behavior and impulsivity in kleptomania: a pilot study.

    Science.gov (United States)

    Grant, Jon E; Odlaug, Brian L; Schreiber, Liana R N; Chamberlain, Samuel R; Won Kim, Suck

    2013-03-01

    Kleptomania is characterized by repetitive stealing behavior and has been associated with deleterious unwanted outcomes including forensic contact and increased rates of suicidal behavior. Very few trials have been conducted to investigate pharmacological treatment options for this neglected condition. Memantine is an NMDA-receptor antagonist that has shown promising results in the treatment of other behavioral addictions and substance addictions. Twelve individuals with kleptomania received memantine (10 mg/day, titrated to 30 mg/day maximum depending on clinical response and tolerability) over the course of 8 weeks, in an open-label trial. The effects of treatment were quantified using well-validated measures and select neurocognitive tests (last observation carried forward analyses). Kleptomania disease severity scores decreased across all measures considered, and 11 (91.7%) of the participants met the responder criteria (35% improvement on the primary effectiveness measure plus CGI improved/very much improved; significant improvements were also observed in terms of mood, anxiety, and disability scores along with a significant improvement in stop-signal response inhibition. Memantine was generally well tolerated. This study shows the effectiveness of memantine in reducing urges to shoplift and shoplifting behavior along with improving impulsivity, mood, anxiety, and psychosocial functioning.

  7. Effectiveness of Memantine in Improvement of Cognitive Deficits in Specific Learning Disorder

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    Elham Ahmadi Zahrani

    2016-12-01

    Full Text Available Abstract Background: Specific learning disorder is a neurodevelopmental disorder characterized by persistent difficulties in learning academic skills in reading, written expression, or mathematics. This study was performed to investigate the effectiveness of memantine in the relief of cognitive deficits (selective attention, sustained attention, and working memory in specific learning disorder. Materials and Methods: This study is a clinical trial. Of all children 8-12 years referred to Amir Kabir Hospital 94 patients diagnosed with specific learning disorder based on DSMV diagnostic interview referred by specialist and randomly divided by two groups, memantine and placebo. Cognitive deficits before and after treatment were measured with continuous performance test, Stroop test and Wechsler Digit Span forward and reverse and Corsi test. Results: Multivariate analysis of variance showed a significant difference in error when answering, omission answer and corrected answer in continuous performance test, but this difference is not significant in response time. Difference in forward, reverse and collected auditory was significant and not significant in the auditory span. In active visual working memory at corsi cube test, difference was significant (p <0.05. Conclusion: The results showed that memantine in improvement of sustained attention, auditory working memory and visual working memory, is effective, while in selective attention is not effective and according to similarities of learning disorder and Attention deficit / Hyperactivity disorder (ADHD and the effectiveness of memantine in improvement of symptoms of ADHD, we can also use this drug in improvement of cognitive deficits of specific learning disorder.

  8. An Open-Label Trial of Memantine for Cognitive Impairment in Patients with Posttraumatic Stress Disorder

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    Sriram Ramaswamy

    2015-01-01

    Full Text Available Background. Studies using standard neuropsychological instruments have demonstrated memory deficits in patients with PTSD. We evaluated the efficacy and safety of the N-methyl-D-aspartate antagonist memantine in veterans with PTSD and cognitive impairment. Methods. Twenty-six veterans with PTSD and cognitive impairment received 16 weeks of memantine in an open-label fashion. Cognition was assessed using the Spatial Span, Logical Memory I, and Letter-Number Sequencing subtests of the Wechsler Memory Scale III and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS. RBANS measures attention, language, visuospatial skills, and immediate and delayed memories. The Clinician Administered PTSD Scale (CAPS, Hamilton Depression Scale (HAM-D, Hamilton Anxiety Scale (HAM-A, Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q, and Sheehan Disability Scale (SDS were secondary outcome measures. Results. There was a significant improvement in RBANS, both total and subscale scores (P<0.05, over time. There was a reduction in total CAPS scores, avoidance/numbing symptoms (CAPS-C and hyperarousal symptoms (CAPS-D, HAM-D, Q-LES-Q, and SDS scores. However, there was no reduction in reexperiencing (CAPS-B and HAM-A scores. Memantine was well tolerated. Conclusions. Memantine improved cognitive symptoms, PTSD symptoms, and mood in veterans with PTSD. Randomized double-blind studies are needed to validate these preliminary observations.

  9. [Assessment of benefits of drug therapies: memantine for Alzheimer's disease as an example].

    Science.gov (United States)

    Rüther, E; Hellweg, R; Janetzky, W

    2012-12-01

    After the approval of a drug, which represents a first assessment, independent institutions and medical professional associations provide further evaluations. Here, the question is to be asked whether common or diverging evaluation methods exist that can have an impact on the result. In principle, two methods are used: meta-analyses and responder analyses. Meta-analyses and the resulting effect sizes have to be interpreted according to the field of application (for example, the type and severity degree of a disease) with medical expertise. Omitting this can lead to incorrect evaluations and to a discrepancy of evaluation results. In the case of memantine, the merely biometric evaluation of meta-analyses performed by the IQWiG led to a denial of the benefit, while the same data, considering clinical routine, led professional associations to recommend memantine for moderate to severe Alzheimer´s disease. In contrast to meta-analyses, responder analyses directly show the benefit of a therapy option in the presence of significant group differences, as the selected responder criteria are based on the indication. The corresponding results of the responder analyses on memantine were also acknowledged by the IQWiG and led to a positive evaluation of memantine. This discrepancy of evaluation results illustrates the fact that statistical procedures are necessary when evaluating drug and non-drug therapy options but, that the interpretation of the results with medical expertise is essential. © Georg Thieme Verlag KG Stuttgart · New York.

  10. The effects of memantine on recovery, cognitive functions, and pain after propofol anesthesia

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    Ulku Emik

    Full Text Available Abstract Objectives: Postoperative cognitive dysfunction refers to the problems associated with thought and memory that are often experienced after major surgery. The aim of this study is to evaluate the effects of intraperitoneally administered memantine on recovery, cognitive functions, and pain after propofol anesthesia. Methods: The study was conducted in Gazi University Animal Research Laboratory, Ankara, Turkey in January 2012. Twenty-four adult female Wistar Albino rats weighing 170-270 g were educated for 300 s in the radial arm maze (RAM over three days. Group P was administered 150 mg kg−1 of intraperitoneal (IP propofol; Group M was given 1 mg kg−1 of IP memantine; and Group MP was given 1 mg kg−1 of IP memantine before being administered 150 mg kg−1 of IP propofol. The control group received only IP saline. RAM and hot plate values were obtained after recovery from the groups that received propofol anesthesia and 30 min after the administration of drugs in other two groups. Results: The duration of recovery for Group MP was significantly shorter than Group P (p < 0.001, and the number of entries and exits in the RAM by Group MP was significantly higher during the first hour when compared to Group P (p < 0.0001. Hot plate values, on the other hand, were found to be significantly increased in all groups when compared to the control values, aside from Group C (p < 0.0001. Conclusion: In this study, memantine provided shorter recovery times, better cognitive functions, and reduced postoperative pain. From this study, we find that memantine has beneficial effects on recovery, cognitive functions, and pain after propofol anesthesia.

  11. Bilateral brain reorganization with memantine and constraint-induced aphasia therapy in chronic post-stroke aphasia: An ERP study.

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    Barbancho, Miguel A; Berthier, Marcelo L; Navas-Sánchez, Patricia; Dávila, Guadalupe; Green-Heredia, Cristina; García-Alberca, José M; Ruiz-Cruces, Rafael; López-González, Manuel V; Dawid-Milner, Marc S; Pulvermüller, Friedemann; Lara, J Pablo

    2015-01-01

    Changes in ERP (P100 and N400) and root mean square (RMS) were obtained during a silent reading task in 28 patients with chronic post-stroke aphasia in a randomized, double-blind, placebo-controlled trial of both memantine and constraint-induced aphasia therapy (CIAT). Participants received memantine/placebo alone (weeks 0-16), followed by drug treatment combined with CIAT (weeks 16-18), and then memantine/placebo alone (weeks 18-20). ERP/RMS values (week 16) decreased more in the memantine group than in the placebo group. During CIAT application (weeks 16-18), improvements in aphasia severity and ERP/RMS values were amplified by memantine and changes remained stable thereafter (weeks 18-20). Changes in ERP/RMS occurred in left and right hemispheres and correlated with gains in language performance. No changes in ERP/RMS were found in a healthy group in two separated evaluations. Our results show that aphasia recovery induced by both memantine alone and in combination with CIAT is indexed by bilateral cortical potentials. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer’s Disease: A Review of Clinical Trials

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    Ivana Molino

    2013-01-01

    Full Text Available Background. Acetylcholinesterase (AChE/cholinesterase (ChE inhibitors (Is and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer’s disease (AD, respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks, and the different cognitive assessment tools used did not allow comparing properly different trials.

  13. Efficacy of Memantine, Donepezil, or Their Association in Moderate-Severe Alzheimer's Disease: A Review of Clinical Trials

    Science.gov (United States)

    Molino, Ivana; Colucci, Luisa; Fasanaro, Angiola M.

    2013-01-01

    Background. Acetylcholinesterase (AChE)/cholinesterase (ChE) inhibitors (Is) and memantine are licensed for symptomatic treatment of mild-moderate and moderate-severe forms of Alzheimer's disease (AD), respectively. High doses of the AChE-I donepezil were licensed in the USA for moderate-severe AD, and the association AChE/ChE-Is plus memantine was proposed for AD at this stage. Objectives. This paper has reviewed evidence from clinical trials of the effectiveness of memantine, donepezil, or the two drugs in association in managing moderate-severe AD. Method. Double-blind, placebo-controlled randomized trials (RCTs) using memantine or donepezil alone or in association versus placebo in moderate-severe AD were reviewed. Analysis done in January 2013 considered the years 2007–2012. Results and Conclusion. Only 83 of the 941 papers selected were considered relevant, and only 13 met the criterion of “adequacy and representativeness.” Memantine and donepezil lead to improvements in moderate-to-severe AD and the choice between the compounds should be based on their contraindications more than on disease severity. No evidence was found of advantages of the association of memantine-donepezil. The heterogeneity of conditions explored by RCTs, the relatively short time of observation (24–52 weeks), and the different cognitive assessment tools used did not allow comparing properly different trials. PMID:24288512

  14. Lithium and memantine improve spatial memory impairment and neuroinflammation induced by β-amyloid 1-42 oligomers in rats.

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    Budni, J; Feijó, D P; Batista-Silva, H; Garcez, M L; Mina, F; Belletini-Santos, T; Krasilchik, L R; Luz, A P; Schiavo, G L; Quevedo, J

    2017-05-01

    Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The main hallmarks of this disease include progressive cognitive dysfunction and an accumulation of soluble oligomers of β-amyloid (Aβ) 1-42 peptide. In this research, we show the effects of lithium and memantine on spatial memory and neuroinflammation in an Aβ1-42 oligomers-induced animal model of dementia in rats. Aβ 1-42 oligomers were administered intrahippocampally to male wistar rats to induce dementia. Oral treatments with memantine (5mg/kg), lithium (5mg/kg), or both drugs in combination were performed over a period of 17days. 14days after the administration of the Aβ1-42 oligomers, the radial arm-maze task was performed. At the end of the test period, the animals were euthanized, and the frontal cortex and hippocampus were removed for use in our analysis. Our results showed that alone treatments with lithium or memantine ameliorate the spatial memory damage caused by Aβ1-42. The animals that received combined doses of lithium and memantine showed better cognitive performance in their latency time and total errors to find food when compared to the results from alone treatments. Moreover, in our study, lithium and/or memantine were able to reverse the decreases observed in the levels of interleukin (IL)-4 that were induced by Aβ1-42 in the frontal cortex. In the hippocampus, only memantine and the association of memantine and lithium were able to reverse this effect. Alone doses of lithium and memantine or the association of lithium and memantine caused reductions in the levels of IL-1β in the frontal cortex and hippocampus, and decreased the levels of TNF-α in the hippocampus. Taken together, these data suggest that lithium and memantine might be a potential therapy against cognitive impairment and neuroinflammation induced by Aβ1-42, and their association may be a promising alternative to be investigated in the treatment of AD-like dementia. Copyright © 2017 Elsevier

  15. Effect of memantine on CBF and CMRO2 in patients with early Parkinson's disease

    DEFF Research Database (Denmark)

    Borghammer, P; Vafaee, M; Ostergaard, K

    2008-01-01

    Objectives –  Parkinson’s disease (PD) may be associated with increased energy metabolism in overactive regions of the basal ganglia. Therefore, we hypothesized that treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine would decrease regional cerebral blood flow (r......CBF) and oxygen metabolism in the basal ganglia of patients with early-stage PD. Methods –  Quantitative positron emission tomography (PET) recordings were obtained with [15O]water and [15O]oxygen in 10 patients, scanned first in a baseline condition, and again 6 weeks after treatment with a daily dose of 20 mg...... memantine. Dynamic PET data were analyzed using volume of interest and voxel-based approaches. Results –  The treatment evoked rCBF decreases in basal ganglia, and in several frontal cortical areas. The regional cerebral metabolic rate of oxygen (rCMRO2) did not decrease in any of the a priori defined...

  16. Memantine shows promise in reducing gambling severity and cognitive inflexibility in pathological gambling: a pilot study.

    Science.gov (United States)

    Grant, Jon E; Chamberlain, Samuel R; Odlaug, Brian L; Potenza, Marc N; Kim, Suck Won

    2010-12-01

    Although pathological gambling (PG) is relatively common, pharmacotherapy research for PG is limited. Memantine, an N-methyl D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive decision making, suggesting it may help individuals with PG. This study sought to examine the safety and efficacy of Memantine in PG. Twenty-nine subjects (18 females) with DSM-IV PG were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/day). Subjects were enrolled from January 2009 until April 2010. Change from baseline to study endpoint on the Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling (PG-YBOCS) was the primary outcome measure. Subjects underwent pre- and post-treatment cognitive assessments using the stop-signal task (assessing response impulsivity) and the intra-dimensional/extra-dimensional (ID/ED) set shift task (assessing cognitive flexibility). Twenty-eight of the 29 subjects (96.6%) completed the 10-week study. PG-YBOCS scores decreased from a mean of 21.8 ± 4.3 at baseline to 8.9 ± 7.1 at study endpoint (p gambling per week and money spent gambling both decreased significantly (p medication was well-tolerated. Memantine treatment was associated with diminished gambling and improved cognitive flexibility. These findings suggest that pharmacological manipulation of the glutamate system may target both gambling and cognitive deficits in PG. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

  17. Study of the effect of memantine therapy on the treatment of dyslexia in children

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    Mojgan Karahmadi

    2017-01-01

    Full Text Available Background: Reading disorder (RD is one of the important complaints in children with learning disorders (LD that is prevalent in 4% of children in the United States. Treating this disorder includes education of reading practices and treating psychological disorders, and there are no exact medications prescribed in these children. Memantine has been effective in treating memory problems in Alzheimer Dementia, obsessive–compulsive disorder, autism disorder, and other psychological diseases. The aim of this study is to evaluate the effect of memantine in improving RD in children. Materials and Methods: In this randomized clinical trial, 62 children, with RD in Pediatric Psychiatry Clinics of Noor and Ali-Asghar Hospital in Isfahan from 2015 to 2016, were participated. They were randomly assigned to two groups of equal number, one receiving education plus memantine and the other education plus placebo. RD was evaluated at the beginning, 1 and 3 months after intervention by Iranian standard reading and dyslexia test (Nama. Results: Mean (standard deviation age of participants was 7.55 (0.60 years. Most of the participants were boy (55%, most having parents in 36–45-year-old age group (52% and 48% for fathers and mothers, respectively, and also most parents in diploma and bachelor educational group (61% and 60% for fathers and mothers, respectively. There were statistical significant difference in trend of total score (P = 0.034, word chain (P < 0.001, rhyming (P < 0.001, text comprehension (P < 0.001, and letter fluency (P = 0.002, subscale between two groups. However, the difference of time trend between two groups was not significant in word reading (P = 0.14, word comprehension (P = 0.06, phoneme deletion (P = 0.12, reading nonwords (P = 0.32, and category fluency (P = 0.06. Conclusion: Adding memantine to educational practices is effective in improving RD in school-age children with LD.

  18. Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension.

    Science.gov (United States)

    Aman, Michael G; Findling, Robert L; Hardan, Antonio Y; Hendren, Robert L; Melmed, Raun D; Kehinde-Nelson, Ola; Hsu, Hai-An; Trugman, Joel M; Palmer, Robert H; Graham, Stephen M; Gage, Allyson T; Perhach, James L; Katz, Ephraim

    2017-06-01

    Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension. A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day. There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks. This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

  19. Pigment epithelium-derived factor up-regulation induced by memantine, an N-methyl-D-aspartate receptor antagonist, is involved in increased proliferation of hippocampal progenitor cells.

    Science.gov (United States)

    Namba, T; Yabe, T; Gonda, Y; Ichikawa, N; Sanagi, T; Arikawa-Hirasawa, E; Mochizuki, H; Kohsaka, S; Uchino, S

    2010-05-05

    Memantine is classified as an NMDA receptor antagonist. We recently reported that memantine promoted the proliferation of neural progenitor cells and the production of mature granule neurons in the adult hippocampus. However, the molecular mechanism responsible for the memantine-induced promotion of cellular proliferation remains unknown. In this study we searched for a factor that mediates memantine-induced cellular proliferation, and found that pigment epithelium-derived factor (PEDF), a broad-acting neurotrophic factor, is up-regulated in the dentate gyrus of adult mice after the injection of memantine. PEDF mRNA expression increased significantly by 3.5-fold at 1 day after the injection of memantine. In addition, the expression level of PEDF protein also increased by 1.8-fold at 2 days after the injection of memantine. Immunohistochemical study using anti-PEDF antibody showed that the majority of the PEDF-expressing cells were protoplasmic and perivascular astrocytes. Using a neurosphere assay, we confirmed that PEDF enhanced cellular proliferation under the presence of fibroblast growth factor-2 (FGF-2) and epidermal growth factor (EGF) but was not involved in the multilineage potency of hippocampal progenitor cells. Over expression of PEDF by adeno-associated virus, however, did not stimulate cellular proliferation, suggesting PEDF per se does not promote cellular proliferation in vivo. These findings suggest that the memantine induced PEDF up-regulation is involved in increased proliferation of hippocampal progenitor cells. (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. MEMANTINE ATTENUATES THE OKADAIC ACID INDUCED SHORT-TERM SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS IN RATS.

    Science.gov (United States)

    Dashniani, M; Chighladze, M; Burjanadze, M; Beselia, G; Kruashvili, L

    2016-03-01

    In the present study, the possible beneficial effect of memantine on the Okadaic Acid (OA) induced spatial short-term memory impairment was examined in spatial alternation task, and the neuroprotective potential of memantine on OA-induced structural changes in the hippocampus was evaluated by Nissl staining. OA was dissolved in artificial cerebrospinal fluid (aCSF) and injected intracerebroventriculary (ICV) 200 ng in a volume of 10 μl bilaterally. Vehicle control received aCSF ICV bilaterally. Control and OA injected rats were divided into 2 subgroups injected i.p. with saline or memantine (5 mg/kg). Memantine or saline were given daily for 13 days starting from the day of OA injection. Behavioral study showed that bilateral ICV microinjection of OA induced impairment in spatial short-term memory. Nissl staining in the present study showed that the ICV microinjection of OA significantly decreased the number of surviving pyramidal neurons in the CA1 region of the hippocampus. Chronic administration of memantine effectively attenuated OA induced spatial short-term memory impairment and the OA-induced neuropathological changes in the hippocampus. Therefore, ICV injection of OA can be used as an experimental model to study mechanisms of neurodegeneration and define novel therapeutics targets for AD pathology.

  1. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: A meta-analysis.

    Directory of Open Access Journals (Sweden)

    Ruey Chen

    Full Text Available This is the first meta-analysis to compare the treatment effects and safety of administering donepezil alone versus a combination of memantine and donepezil to treat patients with moderate to severe Alzheimer Disease, particularly regarding cognitive functions, behavioral and psychological symptoms in dementia (BPSD, and global functions.PubMed, Medline, Embase, PsycINFO, and Cochrane databases were used to search for English and non-English articles for inclusion in the meta-analysis to evaluate the effect size and incidence of adverse drug reactions of different treatments.Compared with patients who received donepezil alone, those who received donepezil in combination with memantine exhibited limited improvements in cognitive functions (g = 0.378, p < .001, BPSD (g = -0.878, p < .001 and global functions (g = -0.585, p = .004. Gradual titration of memantine plus a fixed dose and gradual titration of donepezil as well as a fixed dose and gradual titration of memantine resulted in limited improvements in cognitive functions(g = 0.371, p = .005, BPSD(g = -0.913, p = .001, and global functions(g = -0.371, p = .001.Both in the 24th week and at the final evaluation point, the combination of donepezil and memantine led to greater improvement in cognitive functions, BPSD, and global functions than did donepezil alone in patients with moderate to severe Alzheimer Disease.

  2. Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

    Science.gov (United States)

    Knapp, Martin; King, Derek; Romeo, Renée; Adams, Jessica; Baldwin, Ashley; Ballard, Clive; Banerjee, Sube; Barber, Robert; Bentham, Peter; Brown, Richard G; Burns, Alistair; Dening, Tom; Findlay, David; Holmes, Clive; Johnson, Tony; Jones, Robert; Katona, Cornelius; Lindesay, James; Macharouthu, Ajay; McKeith, Ian; McShane, Rupert; O'Brien, John T; Phillips, Patrick P J; Sheehan, Bart; Howard, Robert

    2017-12-01

    Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd.

  3. Memantine add-on to antipsychotic treatment for residual negative and cognitive symptoms of schizophrenia: a meta-analysis.

    Science.gov (United States)

    Kishi, Taro; Matsuda, Yuki; Iwata, Nakao

    2017-07-01

    We examined whether memantine add-on to antipsychotic treatment is beneficial in schizophrenia treatment. This systematic review and meta-analysis aimed to achieve stronger evidence on the efficacy and safety of memantine add-on for treating schizophrenia. We analyzed double-blind, randomized, placebo-controlled trials of memantine add-on treatment in schizophrenia patients receiving antipsychotics. The primary outcomes were amelioration of negative symptoms and all-cause discontinuation. Dichotomous outcomes are presented as risk ratios (RRs), and continuous outcomes are presented as mean differences (MDs) or standardized mean differences (SMDs). Eight studies (n = 448) were included. Although memantine add-on treatment was superior to placebo for ameliorating negative symptoms (SMD = -0.96, p = 0.006, I 2  = 88%; N = 7, n = 367) in the Positive and Negative Syndrome Scale general subscale (MD = -1.62, p = 0.002, I 2  = 0%; N = 4, n = 151) and Mini-Mental Status Examination score (MD = -3.07, p add-on treatment remained superior to placebo (SMD = -1.29, p = 0.00001). Meta-regression analysis showed that patient age was associated with memantine-associated amelioration of negative symptoms (slope = 0.171, p = 0.0206). Memantine add-on treatment may be beneficial for treating psychopathological symptoms (especially negative symptoms) in schizophrenia patients. The negative-symptom effect size may be associated with younger adult schizophrenia patients.

  4. Cost-utility analysis of memantine extended release added to cholinesterase inhibitors compared to cholinesterase inhibitor monotherapy for the treatment of moderate-to-severe dementia of the Alzheimer's type in the US.

    Science.gov (United States)

    Saint-Laurent Thibault, Catherine; Özer Stillman, Ipek; Chen, Stephanie; Getsios, Denis; Proskorovsky, Irina; Hernandez, Luis; Dixit, Shailja

    2015-01-01

    This study evaluates the cost-effectiveness of memantine extended release (ER) as an add-on therapy to acetylcholinesterase inhibitor (AChEI) [combination therapy] for treatment of patients with moderate-to-severe Alzheimer's disease (AD) from both a healthcare payer and a societal perspective over 3 years when compared to AChEI monotherapy in the US. A phase III trial evaluated the efficacy and safety of memantine ER for treatment of AD patients taking an AChEI. The analysis assessed the long-term costs and health outcomes using an individual patient simulation in which AD progression is modeled in terms of cognition, behavior, and functioning changes. Input parameters are based on patient-level trial data, published literature, and publicly available data sources. Changes in anti-psychotic medication use are incorporated based on a published retrospective cohort study. Costs include drug acquisition and monitoring, total AD-related medical care, and informal care associated with caregiver time. Incremental cost-utility ratio (ICUR), life years, care time for caregiver, time in community and institution, time on anti-psychotics, time by disease severity, and time without severe symptoms are reported. Costs and health outcomes are discounted at 3% per annum. Considering a societal perspective over 3 years, this analysis shows that memantine ER combined with an AChEI provides better clinical outcomes and lower costs than AChEI monotherapy. Discounted average savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life-years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively. Patients on combination therapy spent an average of 4 months longer living at home and spend less time in moderate-severe and severe stages of the disease. Combination therapy for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

  5. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

    Directory of Open Access Journals (Sweden)

    Hongen Wei

    Full Text Available Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs from Fmr1 knockout (KO mice, a mouse model for fragile X syndrome (FXS and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

  6. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

    Science.gov (United States)

    Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

    2012-01-01

    Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

  7. Amyloid-beta immunotherapy: the hope for Alzheimer disease?

    Science.gov (United States)

    Barrera-Ocampo, Alvaro; Lopera, Francisco

    2016-12-30

    Alzheimer disease (AD) is the most prevalent form of dementia of adult-onset, characterized by progressive impairment in cognition and memory. There is no cure for the disease and the current treatments are only symptomatic. Drug discovery is an expensive and time-consuming process; in the last decade no new drugs have been found for AD despite the efforts of the scientific community and pharmaceutical companies. The Aβ immunotherapy is one of the most promising approaches to modify the course of AD. This therapeutic strategy uses synthetic peptides or monoclonal antibodies (mAb) to decrease the Aβ load in the brain and slow the progression of the disease. Therefore, this article will discuss the main aspects of AD neuropathogenesis, the classical pharmacologic treatment, as well as the active and passive immunization describing drug prototypes evaluated in different clinical trials.

  8. Glutamate carboxypeptidase II does not process amyloid-beta peptide

    Czech Academy of Sciences Publication Activity Database

    Sedlák, František; Šácha, Pavel; Blechová, Miroslava; Březinová, Anna; Šafařík, Martin; Šebestík, Jaroslav; Konvalinka, Jan

    2013-01-01

    Roč. 27, č. 7 (2013), s. 2626-2632 ISSN 0892-6638 R&D Projects: GA ČR GAP304/12/0847 Institutional support: RVO:61388963 Keywords : PSMA * Alzheimer's disease * disaggregation * exopeptidase * substrate specificity * depsipeptide Subject RIV: CE - Biochemistry Impact factor: 5.480, year: 2013

  9. Imaging amyloid beta peptide oligomeric particles in solution.

    Science.gov (United States)

    Dong, Jijun; Apkarian, Robert P; Lynn, David G

    2005-09-01

    While all protein misfolding diseases are characterized by fibrous amyloid deposits, the favorable free energy and strongly cooperative nature of the self-assembly have complicated the development of therapeutic strategies aimed at preventing their formation. As structural models for the amyloid fibrils approach atomic resolution, increasing evidence suggests that early folding intermediates, rather than the final structure, are more strongly associated with the loss of neuronal function. For that reason we now demonstrate the use of cryo-etch high-resolution scanning electron microscopy (cryo-HRSEM) for the direct observation of pathway intermediates in amyloid assembly. A congener of the Abeta peptide of Alzheimer's disease, Abeta(13-21), samples a variety of time-dependent self-assembles in a manner similar to those seen for larger proteins. A morphological description of these intermediates is the first step towards their structural characterization and the definition of their role in both amyloid assembly and neurotoxicity.

  10. Changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy. A preliminary study

    International Nuclear Information System (INIS)

    Kim, Yong-Wook; Shin, Ji-Cheol; An, Young-Sil

    2010-01-01

    The objective of this study was to investigate the changes in cerebral glucose metabolism in patients with posttraumatic cognitive impairment after memantine therapy. We performed serial F-18 fluorodeoxyglucose positron emission tomography studies before and after memantine therapy (20 mg per day) on 17 patients with posttraumatic cognitive impairment using statistical parametric mapping analysis. In addition, covariance analysis was performed to identify regions, where changes in regional cerebral glucose metabolism correlated significantly with increased Mini-Mental Status Examination scores. Statistical parametric mapping analysis demonstrated that, compared with baseline, significantly increased cerebral glucose metabolism occurred in both inferior, middle and superior frontal gyri, both angular gyri, both precuneus, the right middle cingulum, the left inferior parietal lobule, the left fusiform gyrus, the left precentral gyrus, the left paracentral lobule, and the left lingual gyrus after memantine therapy (P uncorrected uncorrected corrected <0.0001). Our findings indicate that the prefrontal and the parietal association cortices may be the relevant structures for the pharmacological response to memantine therapy in patients with posttraumatic cognitive impairment. (author)

  11. Memantine for prophylaxis of chronic tension-type headache--a double-blind, randomized, crossover clinical trial

    DEFF Research Database (Denmark)

    Lindelof, K; Bendtsen, L; Lindelof, K

    2009-01-01

    Treatment for chronic tension-type headache (CTTH) is unsatisfactory. Our aim was to investigate the efficacy of the N-methyl D-aspartate (NMDA) antagonist memantine in the prophylactic treatment of CTTH. We included 40 patients in a randomized, double-blind, placebo-controlled, crossover trial...

  12. Efficacy and Tolerability of a Combination Treatment of Memantine and Donepezil for Alzheimer’s Disease: A Literature Review Evidence

    Science.gov (United States)

    Riverol, Mario; Slachevsky, Andrea; López, Oscar L.

    2011-01-01

    INTRODUCTION Two types of drugs have been approved for the symptomatic treatment of Alzheimer’s disease (AD): the cholinesterase inhibitors (ChEIs) and memantine. There is a growing interest to know whether the combination of these drugs is safe and if it adds any clinical benefit to patients. OBJECTIVE To systematically review published medical literature assessing the efficacy and tolerability of a combination treatment of memantine and donepezil in AD patients. METHODS We searched PubMed for English and Spanish-language literature, using the terms “Alzheimer’s disease,” “cholinesterase inhibitors,” “donepezil,” and “memantine.” Our review focused on clinical trials and observational studies. RESULTS Eleven publications representing seven unique studies were selected for this review. Three were randomized double-blind, placebo-controlled trials and four were observational studies. CONCLUSIONS Available data revealed that the combination of memantine and donepezil slowed down cognitive decline, prolonged functional independence, and improved behavioral symptoms in patients with moderate to severe AD. The long-term use of the dual therapy decreased the risk of nursing home admission. More longitudinal studies are needed to further examine the role of combined therapy in the management of AD patients. PMID:25302109

  13. Open-label pilot study of memantine in the treatment of compulsive buying.

    Science.gov (United States)

    Grant, Jon E; Odlaug, Brian L; Mooney, Marc; O'Brien, Robert; Kim, Suck Won

    2012-05-01

    Although compulsive buying (CB) is relatively common, pharmacotherapy research for CB is limited. Memantine, an N-methyl-D-aspartate receptor antagonist, appears to reduce glutamate excitability and improve impulsive behaviors, suggesting it may help individuals with CB. Nine patients (8 females) with CB were enrolled in a 10-week open-label treatment study of memantine (dose ranging from 10 to 30 mg/d). Participants were enrolled from December 2008 until May 2010. The primary outcome measure was change from baseline to study endpoint on the Yale-Brown Obsessive Compulsive Scale-Shopping Version (Y-BOCS-SV). Of the 9 participants, 8 (88.9%) completed the 10-week study. Y-BOCS-SV scores decreased from a mean of 22.0 ± 1.3 at baseline to 11.0 ± 5.3 at endpoint (P buying and improvements on cognitive tasks of impulsivity. In addition, the medication was well-tolerated. These findings suggest that pharmacologic manipulation of the glutamate system may target the impulsive behavior underlying CB. Placebo-controlled, double-blind studies are warranted in order to confirm these preliminary findings in a controlled design.

  14. Management of moderate to severe Alzheimer’s disease: Focus on memantine

    Directory of Open Access Journals (Sweden)

    Evangelyn Dominguez

    2011-12-01

    Full Text Available Alzheimer’s disease (AD is the most common form of dementia, and one of the principal causes leading to death around the world. It is a progressive neurodegenerative disorder that still remains without definite cure. Memantine, a licensed AD drug, is an open-channel and partial trapping blocker that functions as a potent NMDA receptor antagonist, even at low concentrations. Aside from being uncompetitive, it also allows near-normal physiological NMDA receptor activity throughout the brain even with high glutamate concentrations, making it more reliable and tolerable than other AD-targeted drugs. It has also been found to be effective, safe, and well-tolerated in animal models as well as patients with moderate-to-severe AD. Aside from NMDA receptor antagonism, numerous studies have reported that memantine can also affect dopamine receptors, block excessive calcium influx and production of reactive oxygen species (ROS induced by Aβ oligomers, and inhibit the internal ribosome entry site (IRES, thus preventing the expression of the amyloid precursor and tau proteins which are considered as early indicators of Alzheimer's.

  15. Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice.

    Science.gov (United States)

    Yabuki, Yasushi; Matsuo, Kazuya; Hirano, Koga; Shinoda, Yasuharu; Moriguchi, Shigeki; Fukunaga, Kohji

    2017-01-01

    Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, and the cholinesterase inhibitor, donepezil, are approved in most countries for treating moderate-to-severe Alzheimer's disease (AD). These drugs have different molecular targets; thus, it is expected that the effects of combined treatment would be synergistic. Some reports do show memantine/donepezil synergy in ameliorating cognition in AD model animals, but their combined effects on behavioral and psychological symptoms of dementia (BPSD)-like behaviors have not been addressed. Here, we investigate combined memantine/donepezil effects on cognitive impairment and BPSD-like behaviors in olfactory bulbectomized (OBX) mice. Interestingly, combined administration synergistically improved both depressive-like behaviors and impaired social interaction in OBX mice, whereas only weak synergistic effects on cognitive performance were seen. To address mechanisms underlying these effects, we used in vivo microdialysis study and observed impaired nicotine-induced serotonin (5-HT) release in OBX mouse hippocampus. Combined memantine/donepezil administration, but not single administration of either, significantly antagonized the decrease in nicotine-induced 5-HT release seen in OBX mouse hippocampus. Furthermore, decreased autophosphorylation of calcium/calmodulin dependent protein kinase II (CaMKII) was rescued in hippocampal CA1 and dentate gyrus of OBX mice by combined memantine/donepezil administration. These results suggest that improvement of BPSD-like behaviors by the co-administration of both drugs is in part mediated by enhanced 5-HT release and CaMKII activity in OBX mouse hippocampus. © 2016 S. Karger AG, Basel.

  16. Nursing home placement in the Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial: secondary and post-hoc analyses.

    Science.gov (United States)

    Howard, Robert; McShane, Rupert; Lindesay, James; Ritchie, Craig; Baldwin, Ashley; Barber, Robert; Burns, Alistair; Dening, Tom; Findlay, David; Holmes, Clive; Jones, Robert; Jones, Roy; McKeith, Ian; Macharouthu, Ajay; O'Brien, John; Sheehan, Bart; Juszczak, Edmund; Katona, Cornelius; Hills, Robert; Knapp, Martin; Ballard, Clive; Brown, Richard G; Banerjee, Sube; Adams, Jessica; Johnson, Tony; Bentham, Peter; Phillips, Patrick P J

    2015-12-01

    Findings from observational studies have suggested a delay in nursing home placement with dementia drug treatment, but findings from a previous randomised trial of patients with mild-to-moderate Alzheimer's disease showed no effect. We investigated the effects of continuation or discontinuation of donepezil and starting of memantine on subsequent nursing home placement in patients with moderate-to-severe Alzheimer's disease. In the randomised, double-blind, placebo-controlled Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD) trial, community-living patients with moderate-to-severe Alzheimer's disease (who had been prescribed donepezil continuously for at least 3 months at a dose of 10 mg for at least the previous 6 weeks and had a score of between 5 and 13 on the Standardised Mini-Mental State Examination) were recruited from 15 secondary care memory centres in England and Scotland and randomly allocated to continue donepezil 10 mg per day without memantine, discontinue donepezil without memantine, discontinue donepezil and start memantine 20 mg per day, or continue donepezil 10 mg per day and start memantine 20 mg per day, for 52 weeks. After 52 weeks, choice of treatment was left to participants and their physicians. Place of residence was recorded during the first 52 weeks of the trial and then every 26 weeks for a further 3 years. A secondary outcome of the trial, reported in this study, was nursing home placement: an irreversible move from independent accommodation to a residential caring facility. Analyses restricted to risk of placement in the first year of follow-up after the patients had completed the double-blind phase of the trial were post-hoc. The DOMINO-AD trial is registered with the ISRCTN Registry, number ISRCTN49545035. Between Feb 11, 2008, and March 5, 2010, 73 (25%) patients were randomly assigned to continue donepezil without memantine, 73 (25%) to discontinue donepezil without memantine, 76 (26%) to discontinue

  17. The uncompetitive N-methyl-D-aspartate antagonist memantine reduces binge-like eating, food-seeking behavior, and compulsive eating: role of the nucleus accumbens shell.

    Science.gov (United States)

    Smith, Karen L; Rao, Rahul R; Velázquez-Sánchez, Clara; Valenza, Marta; Giuliano, Chiara; Everitt, Barry J; Sabino, Valentina; Cottone, Pietro

    2015-03-13

    Binge-eating disorder is characterized by excessive, uncontrollable consumption of palatable food within brief periods of time. The role of the glutamatergic N-methyl-D-aspartate (NMDA) receptor system in hedonic feeding is poorly understood. The aim of this study was to characterize the effects of the uncompetitive NMDA receptor antagonist memantine on palatable food-induced behavioral adaptations using a rat model, which mimics the characteristic symptomatology observed in binge-eating disorder. For this purpose, we allowed male Wistar rats to respond to obtain a highly palatable, sugary diet (Palatable group) or a regular chow diet (Chow control group), for 1 h a day, under a fixed-ratio 1 (FR1) schedule of reinforcement. Upon stabilization of food responding, we tested the effects of memantine on the Chow and Palatable food groups' intake. Then, we tested the effects of memantine on food-seeking behavior, under a second-order schedule of reinforcement. Furthermore, we investigated the effects of memantine on the intake of food when it was offered in an aversive, bright compartment of a light/dark conflict test. Finally, we evaluated the effects of memantine on FR1 responding for food, when microinfused into the nucleus accumbens (NAcc) shell or core. Memantine dose-dependently decreased binge-like eating and fully blocked food-seeking behavior and compulsive eating, selectively in the Palatable food group. The drug treatment did not affect performance of the control Chow food group. Finally, intra-NAcc shell, but not core, microinfusion of memantine decreased binge-like eating. Together, these findings substantiate a role of memantine as a potential pharmacological treatment for binge-eating disorder.

  18. The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats.

    Science.gov (United States)

    Idrus, Nirelia M; McGough, Nancy N H; Spinetta, Michael J; Thomas, Jennifer D; Riley, Edward P

    2011-01-01

    The third trimester in human fetal development represents a critical time of brain maturation referred to as the "brain growth spurt". This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer's patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. On postnatal day 6, rats were exposed to 6 g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20 mg/kg. Ethanol's teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. Ethanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20 mg/kg memantine during withdrawal significantly attenuated ethanol's adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. These results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Administration of memantine during withdrawal mitigates overactivity and spatial learning impairments associated with neonatal alcohol exposure in rats.

    Science.gov (United States)

    Idrus, Nirelia M; McGough, Nancy N H; Riley, Edward P; Thomas, Jennifer D

    2014-02-01

    Prenatal alcohol exposure can disrupt central nervous system development, manifesting as behavioral deficits that include motor, emotional, and cognitive dysfunction. Both clinical and animal studies have reported binge drinking during development to be highly correlated with an increased risk of fetal alcohol spectrum disorders (FASD). We hypothesized that binge drinking may be especially damaging because it is associated with episodes of alcohol withdrawal. Specifically, we have been investigating the possibility that NMDA receptor-mediated excitotoxicity occurs during alcohol withdrawal and contributes to developmental alcohol-related neuropathology. Consistent with this hypothesis, administration of the NMDA receptor antagonists MK-801 or eliprodil during withdrawal attenuates behavioral alterations associated with early alcohol exposure. In this study, we investigated the effects of memantine, a clinically used NMDA receptor antagonist, on minimizing ethanol-induced overactivity and spatial learning deficits. Sprague-Dawley pups were exposed to 6.0 g/kg ethanol via intubation on postnatal day (PD) 6, a period of brain development that models late gestation in humans. Controls were intubated with a calorically matched maltose solution. During withdrawal, 24 and 36 hours after ethanol exposure, subjects were injected with a total of either 0, 20, or 30 mg/kg memantine. The subjects' locomotor levels were recorded in open field activity monitors on PDs 18 to 21 and on a serial spatial discrimination reversal learning task on PDs 40 to 43. Alcohol exposure induced overactivity and impaired performance in spatial learning. Memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Thus, memantine may be neuroprotective when administered during ethanol withdrawal. These data have important implications for the treatment of EtOH's neurotoxic effects and provide further support that ethanol withdrawal

  20. Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress: implications for memory and behavior.

    Science.gov (United States)

    Amin, Shaimaa Nasr; El-Aidi, Ahmed Amro; Ali, Mohamed Mostafa; Attia, Yasser Mahmoud; Rashed, Laila Ahmed

    2015-06-01

    Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.

  1. Effects of memantine and galantamine given separately or in association, on memory and hippocampal neuronal loss after transient global cerebral ischemia in gerbils.

    Science.gov (United States)

    Lorrio, Silvia; Negredo, Pilar; Roda, José M; García, Antonio G; López, Manuela G

    2009-02-13

    Galantamine is an acetylcholinesterase inhibitor and memantine is a non competitive antagonist of NMDA receptors that are being used to treat Alzheimer's disease (AD) patients. The fact that drugs with different mechanisms of action are available to treat AD introduces the prospect of prescribing drug combinations to amplify drug efficacy. This study was planed to evaluate the potential neuroprotective effects of galantamine combined with memantine in a transient global cerebral ischemia model in gerbils. Animal groups included in the study were: sham, ischemia, and ischemia plus galantamine (1 mg/kg and 10 mg/kg), memantine (10 mg/kg and 20 mg/kg), 1 mg/kg galantamine plus 10 mg/kg memantine, and 10 mg/kg galantamine plus 10 mg/kg memantine, respectively. Surviving pyramidal neurons in the CA1 subfield of the hippocampus, TUNEL, caspase-3 and SOD-2 immunohistochemistries, and the object placement test were evaluated 72 h after reperfusion. Memantine did not exert a clear neuroprotective effect, nor did it prevent spatial memory loss. In a previous study using the same experimental model, galantamine was neuroprotective and improved spatial memory. In this study, the association of 10 mg/kg memantine with 10 mg/kg galantamine increased the number of living pyramidal neurons, reduced TUNEL, active caspase-3 and SOD-2 immunoreactivity, and preserved spatial memory after ischemia-reperfusion injury; however, the effects of the combination were not statistically different from those observed in animals treated with galantamine alone. We believe these results are of interest from a clinical point of view because the association of both drugs is being used in clinical practice and in clinical trials to treat Alzheimer's disease and vascular dementia.

  2. Memantine prevents reference and working memory impairment caused by sleep deprivation in both young and aged Octodon degus.

    Science.gov (United States)

    Tarragon, Ernesto; Lopez, Dolores; Estrada, Cristina; Gonzalez-Cuello, Ana; Ros, Carmen Ma; Lamberty, Yves; Pifferi, Fabien; Cella, Massimo; Canovi, Mara; Guiso, Giovanna; Gobbi, Marco; Fernández-Villalba, Emiliano; Blin, Olivier; Bordet, Regis; Richardson, Jill C; Herrero, María Trinidad

    2014-10-01

    Memory loss is one of the key features of cognitive impairment in either aging, Mild Cognitive Impairment (MCI) or dementia. Pharmacological treatments for memory loss are today focused on addressing symptomatology. One of these approved compounds is memantine, a partial NMDA receptor antagonist that has proved its beneficial effects in cognition. The Octodon degus (O. degus) has been recently proposed as a potential model relevant for neurodegenerative diseases. However, there are no previous studies investigating the effect of pharmacological treatments for age-related cognitive impairment in this rodent. In this work we aimed to evaluate the effect of memantine on sleep deprivation (SD)-induced memory impairment in young and old O. degus. Young and old animals were trained in different behavioral paradigms validated for memory evaluation, and randomly assigned to a control (CTL, n=14) or an SD (n=14) condition, and treated with vehicle or memantine (10-mg/Kg i.p.) before the SD started. We demonstrate that SD impairs memory in both young and old animals, although the effect in the old group was significantly more severe (Pmemories. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Deardorff WJ

    2016-10-01

    Full Text Available William James Deardorff, George T Grossberg Department of Psychiatry, St Louis University School of Medicine, St Louis, MO, USA Abstract: Currently available therapies for the treatment of Alzheimer’s disease (AD consist of cholinesterase inhibitors (ChEIs, such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC of memantine extended-release (ER and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. Keywords: Alzheimer’s disease, cholinesterase inhibitor, donepezil, fixed-dose combination, memantine

  4. Postnatal administration of memantine rescues TNF-α-induced decreased hippocampal precursor proliferation.

    Science.gov (United States)

    Wang, Zhongke; He, Xie; Fan, Xiaotang

    2018-01-01

    Pro-inflammatory cytokine exposure in early postnatal life triggers clear neurotoxic effects on the developing hippocampus. Tumor necrosis factor alpha (TNF-α) is one of the inflammatory mediators and is a potent inhibitor of neurogenesis. Memantine (MEM) is an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist that has been demonstrated to increase the proliferation of hippocampal progenitor cells. However, the effects of MEM on TNF-α-mediated impairment of hippocampal precursor proliferation remain unclear. In this study, mice were exposed to TNF-α and later treated with MEM to evaluate its protective effects on TNF-α-mediated toxicity during hippocampal development. The results indicated that brief exposure to TNF-α on postnatal days 3 and 5 resulted in a significant impairment of hippocampal precursor proliferation and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by MEM treatment. We further confirmed that MEM treatment reversed the TNF-α-induced microglia activation and up-regulation of hippocampal NF-κB, MCP-1 and IL-6 mRNA levels, which may be related to the proliferation and maintenance of NPCs. Overall, our results suggest that MEM treatment protects against TNF-α-induced repression of hippocampal precursor proliferation in postnatal mice by partially attenuating neuroinflammatory responses. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer’s disease receiving donepezil

    Directory of Open Access Journals (Sweden)

    Kano O

    2013-02-01

    Full Text Available Osamu Kano,1 Hirono Ito,1 Takanori Takazawa,1 Yuji Kawase,1 Kiyoko Murata,1 Konosuke Iwamoto,1 Tetsuro Nagaoka,1 Takehisa Hirayama,1 Ken Miura,1 Riya Nagata,1 Tetsuhito Kiyozuka,2 Jo Aoyagi,2 Ryuta Sato,2 Teruo Eguchi,3 Ken Ikeda,1 Yasuo Iwasaki11Department of Neurology, Toho University Omori Medical Center, 2Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations Mishuku Hospital, 3Sakura-kai Medical Group, Tokyo, JapanAbstract: Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-d-aspartate receptor antagonist, memantine, in patients with Alzheimer’s disease (AD. However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10–22 on the Mini-Mental State Examination were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg. Patients with moderate to severe AD (Mini-Mental State Examination scores 3–14 were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen

  6. Memantine protects against amphetamine derivatives-induced neurotoxic damage in rodents.

    Science.gov (United States)

    Chipana, C; Torres, I; Camarasa, J; Pubill, D; Escubedo, E

    2008-06-01

    We hypothesize that 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH) interact with alpha-7 nicotinic receptors (nAChR). Here we examine whether memantine (MEM), an antagonist of NMDAR and alpha-7 nAChR, prevents MDMA and METH neurotoxicity. MEM prevented both serotonergic injury induced by MDMA in rat and dopaminergic lesion by METH in mice. MEM has a better protective effect in front of MDMA- and METH-induced neurotoxicity than methyllycaconitine (MLA), a specific alpha-7 nAChR antagonist. The double antagonism that MEM exerts on NMDA receptor and on alpha-7 nAChR, probably contributes to its effectiveness. MEM inhibited reactive oxygen species production induced by MDMA or METH in synaptosomes. This effect was not modified by NMDA receptor antagonists, but reversed by alpha-7 nAChR agonist (PNU 282987), demonstrating a preventive effect of MEM as a result of it blocking alpha-7 nAChR. In synaptosomes, MDMA decreased 5-HT uptake by about 40%. This decrease was prevented by MEM and by MLA but enhanced by PNU 282987. A similar pattern was observed when we measured the dopamine transport inhibited by METH. The inhibition of both transporters by amphetamine derivatives seems to be regulated by the calcium incorporation after activation of alpha-7 nAChR. MDMA competitively displaces [(3)H]MLA from rat brain membranes. MEM and METH also displace [(3)H]MLA with non-competitive displacement profiles that fit a two-site model. We conclude that MEM prevents MDMA and METH effects in rodents. MEM may offer neuroprotection against neurotoxicity induced by MDMA and METH by preventing the deleterious effects of these amphetamine derivatives on their respective transporters.

  7. Effects of prolonged treatment with memantine in the MRL model of CNS lupus.

    Science.gov (United States)

    Marcinko, Katarina; Parsons, Tiffany; Lerch, Jason P; Sled, John G; Sakic, Boris

    2012-09-01

    Neuropsychiatric manifestations and brain atrophy of unknown etiology are common and severe complications of systemic lupus erythematosus (SLE). An autoantibody that binds to N-methyl-D-aspartate (NMDA) receptor NR2 has been proposed as a key factor in the etiology of central nervous system (CNS) SLE. This hypothesis was supported by evidence suggesting memantine (MEM), an uncompetitive NMDA receptor antagonist, prevents behavioral dysfunction and brain pathology in healthy mice immunized with a peptide similar to an epitope on the NR2 receptor. Given that SLE is a chronic condition, we presently examine the effects of MEM in MRL/lpr mice, which develop behavioral deficits alongside SLE-like disease. A broad behavioral battery and 7-Tesla MRI were used to examine whether prolonged treatment with MEM (~25 mg/kg b.w. in drinking water) prevents CNS involvement in this spontaneous model of SLE. Although MEM increased novel object exploration in MRL/lpr mice, it did not show other beneficial, substrain-specific effects. Conversely, MEM was detrimental to spontaneous activity in control MRL +/+ mice and had a negative effect on body mass gain. Similarly, MRI revealed comparable increases in the volume of periventricular structures in MEM-treated groups. Sustained exposure to MEM affects body growth, brain morphology, and behavior primarily by pharmacological, and not autoimmunity-dependant mechanisms. Substrain-specific improvement in exploratory behavior of MEM-treated MRL/lpr mice may indicate that the NMDA system is merely a constituent of a complex pathogenenic cascade. However, it was evident that chronic administration of MEM is unable to completely prevent the development of a CNS SLE-like syndrome.

  8. Ocular-motor profile and effects of memantine in a familial form of adult cerebellar ataxia with slow saccades and square wave saccadic intrusions.

    Directory of Open Access Journals (Sweden)

    Francesca Rosini

    Full Text Available Fixation instability due to saccadic intrusions is a feature of autosomal recessive spinocerebellar ataxias, and includes square wave intrusions (SWI and macrosaccadic oscillations (MSO. A recent report suggested that the non-competitive antagonist of NMDA receptors, memantine, could decrease MSO and improve fixation in patients with spinocerebellar ataxia with saccadic intrusions (SCASI. We similarly tested two sisters, respectively of 58 and 60 years, with an unrecognized form of recessive, adult-onset cerebellar ataxia, peripheral neuropathy and slow saccades, who showed prominent SWI and also complained with difficulty in reading. We tested horizontal visually guided saccades (10°-18° and three minutes of steady fixation in each patient and in thirty healthy controls. Both patients showed a significant reduction of peak and mean velocity compared with control subjects. Large SWI interrupting steady fixation were prominent during steady fixation and especially following visually guided saccades. Eye movements were recorded before and during the treatment with memantine, 20 mg/daily for 6 months. The treatment with memantine reduced both the magnitude and frequency of SWI (the former significantly, but did not modified neurological conditions or saccade parameters. Thus, our report suggests that memantine may have some general suppressive effect on saccadic intrusions, including both SWI and MSO, thereby restoring the capacity of reading and visual attention in these and in other recessive forms of ataxia, including Friedreich's, in which saccadic intrusions are prominent.

  9. An Open-Label, Multicenter Observational Study for Patients with Alzheimer’s Disease Treated with Memantine in the Clinical Practice

    Directory of Open Access Journals (Sweden)

    S.S. Stamouli

    2011-01-01

    Full Text Available Background/Aims: In this post-marketing observational study, the safety and effectiveness of memantine were evaluated in patients with Alzheimer’s disease (AD. Methods: In a 6-month, observational, open-label study at 202 specialist sites in Greece, the effectiveness of memantine was evaluated using the Mini-Mental State Examination (MMSE and the Instrumental Activities of Daily Living (IADL scale at baseline, and after 3 and 6 months. Discontinuation rates and adverse drug reactions (ADRs were also recorded to evaluate the safety profile of memantine. Results: 2,570 patients participated in the study. Three and 6 months after baseline, MMSE and IADL scores were significantly improved compared to baseline. At the end of the study, 67% of the patients had improved their MMSE score; 7.1% of the patients reported ≧1 ADRs, and treatment was discontinued due to ADR in 0.7%. Conclusion: Memantine was well tolerated and had a positive effect on the patient’s cognitive and functional ability in real-life clinical practice, in agreement with randomized, controlled trials.

  10. A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique

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    Bhavil Narola

    2010-07-01

    Full Text Available This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 µL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 × 4.6 mm, 5 µ. The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N hydrochloric acid, base (1.0 N sodium hydroxide, oxidation (30% hydrogen peroxide, thermal (105°C, photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%, linearity (linearity of range about 70–130 µg/mL, ruggedness (Overall % RSD about 0.35%, stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min. and robustness.

  11. A Validated Stability-indicating Reverse Phase HPLC Assay Method for the Determination of Memantine Hydrochloride Drug Substance with UV-Detection Using Precolumn Derivatization Technique

    Directory of Open Access Journals (Sweden)

    Bhavil Narola

    2010-01-01

    Full Text Available This present paper deals with the development and validation of a stability indicating high performance liquid chromatographic method for the quantitative determination of Memantine hydrochloride. Memantine hydrochloride was derivatized with 0.015 M 9-fluorenylmethyl chloroformate (FMOC and 0.5 M borate buffer solution by keeping it at room temperature for about 20 minutes and the chromatographic separation achieved by injecting 10 μL of the derivatized mixture into a Waters HPLC system with photodiode array detector using a kromasil C18 column (150 × 4.6 mm, 5 μ, The mobile phase consisting of 80% acetonitrile and 20% phosphate buffer solution and a flow rate of 2 milliliter/minute. The Memantine was eluted at approximately 7.5 minutes. The volume of FMOC used in derivatization, concentration of FMOC and derivatization time was optimized and used. Forced degradation studies were performed on bulk sample of Memantine hydrochloride using acid (5.0 Normal (N hydrochloric acid, base (1.0 N sodium hydroxide, oxidation (30% hydrogen peroxide, thermal (105 ° C, photolytic and humidity conditions. The developed LC method was validated with respect to specificity, precision (% RSD about 0.70%, linearity (linearity of range about 70-130 μg/mL, ruggedness (Overall % RSD about 0.35%, stability in analytical solution (Cumulative % RSD about 0.11% after 1450 min. and robustness.

  12. MK-801 and memantine act differently on short-term memory tested with different time-intervals in the Morris water maze test

    Czech Academy of Sciences Publication Activity Database

    Duda, W.; Wesierska, M.; Ostaszewski, P.; Valeš, Karel; Nekovářová, Tereza; Stuchlík, Aleš

    2016-01-01

    Roč. 311, Sep 15 (2016), s. 15-23 ISSN 0166-4328 R&D Projects: GA MŠk(CZ) LH14053; GA ČR(CZ) GA14-03627S Institutional support: RVO:67985823 Keywords : short-term memory * spatial working memory * memantine * dizocilpine * Morris water maze Subject RIV: FH - Neurology Impact factor: 3.002, year: 2016

  13. Memantine, an antagonist of the NMDA glutamate receptor, affects cell proliferation, differentiation and the intracellular cycle and induces apoptosis in Trypanosoma cruzi.

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    Flávia Silva Damasceno

    2014-02-01

    Full Text Available Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi and affects approximately 10 million people in endemic areas of Mexico and Central and South America. Currently available chemotherapies are limited to two compounds: Nifurtimox and Benznidazole. Both drugs reduce the symptoms of the disease and mortality among infected individuals when used during the acute phase, but their efficacy during the chronic phase (during which the majority of cases are diagnosed remains controversial. Moreover, these drugs have several side effects. The aim of this study was to evaluate the effect of Memantine, an antagonist of the glutamate receptor in the CNS of mammals, on the life cycle of T. cruzi. Memantine exhibited a trypanocidal effect, inhibiting the proliferation of epimastigotes (IC50 172.6 µM. Furthermore, this compound interfered with metacyclogenesis (approximately 30% reduction and affected the energy metabolism of the parasite. In addition, Memantine triggered mechanisms that led to the apoptosis-like cell death of epimastigotes, with extracellular exposure of phosphatidylserine, increased production of reactive oxygen species, decreased ATP levels, increased intracellular Ca(2+ and morphological changes. Moreover, Memantine interfered with the intracellular cycle of the parasite, specifically the amastigote stage (IC50 31 µM. Interestingly, the stages of the parasite life cycle that require more energy (epimastigote and amastigote were more affected as were the processes of differentiation and cell invasion.

  14. Critical appraisal of the long-term impact of memantine in treatment of moderate to severe Alzheimer’s disease

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    Umamon Puangthong

    2009-10-01

    Full Text Available Umamon Puangthong, Ging-Yuek Robin HsiungDivision of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, CanadaAbstract: Alzheimer’s disease is the most common cause of dementia in older adults. The clinical features include progressive memory decline as well as cognitive deficits with executive dysfunction, language, visual perceptual difficulties, apraxia and agnosia. During the moderate to severe stage of the disease, there is a major decline in memory and function, while neuropsychiatric disturbances often emerge and patients become difficult to manage. These distressing symptoms increase caregiver burden and add to the direct costs of care of the patients. Any improvements in patient function and behavioral symptoms can reduce caregiver burden. Memantine has been available for a number of years in Europe and in North America. In this article, we examine the pharmacological rationale for its use, and the current clinical evidence for its efficacy and long-term effectiveness in the management of cognitive and behavioral symptoms in moderate to severe stages of Alzheimer’s disease.Keywords: memantine, Alzheimer’s disease, dementia

  15. A fixed-dose combination of memantine extended-release and donepezil in the treatment of moderate-to-severe Alzheimer’s disease

    Science.gov (United States)

    Deardorff, William James; Grossberg, George T

    2016-01-01

    Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified. PMID:27757016

  16. Effectiveness of memantine on depression-like behavior, memory deficits and brain mRNA levels of BDNF and TrkB in rats subjected to repeated unpredictable stress

    DEFF Research Database (Denmark)

    Amidfar, Meysam; Kim, Yong-Ku; Wiborg, Ove

    2018-01-01

    downregulation. Administration of memantine reversed depression-like behavior and memory impairment and significantly increased BDNF and TrkB mRNA levels in both prefrontal cortex and hippocampus of stress exposed rats. CONCLUSIONS: Our study supports the hypothesis that drugs with antagonistic properties...... administration in rats subjected to the repeated unpredictable stress (RUS) paradigm. METHODS: Rats were split into four groups at random including control + saline, control + memantine, stressed + saline and stressed + memantine. After 10 days of exposure to the RUS paradigm, rats were administered memantine...... (20 mg/kg) intraperitoneally (ip) for 14 days. Depression-like behavior and memory performance were assessed by measuring immobility time in the forced swim test and passive avoidance test, respectively. The mRNA levels of BDNF and TrkB in the prefrontal cortex and hippocampus were measured by real...

  17. Treatment of alcohol dependence in patients with co-morbid major depressive disorder – predictors for the outcomes with memantine and escitalopram medication

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    Lönnqvist Jouko

    2008-10-01

    Full Text Available Abstract Background Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine. Methods Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT, Obsessive Compulsive Drinking Scale (OCDS and Drinking Diary. Results The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine. Conclusion Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major

  18. Treatment with UDP-glucose, GDNF, and memantine promotes SVZ and white matter self-repair by endogenous glial progenitor cells in neonatal rats with ischemic PVL.

    Science.gov (United States)

    Li, W-J; Mao, F-X; Chen, H-J; Qian, L-H; Buzby, J S

    2015-01-22

    Periventricular leukomalacia (PVL) is one of the foremost neurological conditions leading to long-term abnormalities in premature infants. Since it is difficult to prevent initiation of this damage in utero, promoting the innate regenerative potential of the brain after birth may provide a more feasible, prospective therapy for PVL. Treatment with UDP-glucose (UDPG), an endogenous agonist of G protein-coupled receptor 17 (GPR17) that may enhance endogenous self-repair potentiality, glial cell line-derived neurotrophic factor (GDNF), a neurotrophic factor associated with the growth and survival of nerve cells, and memantine, a noncompetitive antagonist of N-methyl-d-aspartate (NMDA) receptors that block ischemia-induced glutamate signal transduction, has been reported to achieve functional, neurological improvement in neonatal rats with PVL. The aim of the present study was to further explore whether UDPG, GDNF and/or memantine could promote corresponding self-repair of the subventricular zone (SVZ) and white matter (WM) in neonatal rats with ischemia-induced PVL. SVZ or WM tissue samples and cultured glial progenitor cells derived from a 5 day-old neonatal rat model of PVL were utilized for studying response to UDPG, GDNF and memantine in vivo and in vitro, respectively. Labeling with 5'-bromo-2'-deoxyuridine and immunofluorescent cell lineage markers after hypoxia-ischemia or oxygen-glucose deprivation (OGD) revealed that UDPG, GDNF and memantine each significantly increased glial progenitor cells and preoligodendrocytes (preOLs), as well as more differentiated immature and mature oligodendrocyte (OL), in both the SVZ and WM in vivo or in vitro. SVZ and WM glial cell apoptosis was also significantly reduced by UDPG, GDNF or memantine, both in vivo and in vitro. These results indicated that UDPG, GDNF or memantine may promote endogenous self-repair by stimulating proliferation of glial progenitor cells derived from both the SVZ and WM, activating their

  19. Treatment of alcohol dependence in patients with co-morbid major depressive disorder--predictors for the outcomes with memantine and escitalopram medication.

    Science.gov (United States)

    Muhonen, Leea H; Lahti, Jari; Sinclair, David; Lönnqvist, Jouko; Alho, Hannu

    2008-10-03

    Alcohol dependence comorbid with major depressive disorder poses a major challenge in the clinical setting. The results in the treatment with selective serotonin re-uptake inhibitors have been conflicting. Thus, we compared in alcohol-dependent patients with co-morbid major depressive disorder the selective serotonin re-uptake inhibitor escitalopram to a compound that acts on different transporter system and may reduce craving, the glutamate receptor antagonist memantine. Eighty alcohol-dependent patients comorbid with major depressive disorder in municipal alcohol clinics were randomized 1:1 to receive memantine 20 mg or escitalopram 20 mg in a double-blind manner. During the 26-week study period patients continued their routine treatment at the clinics. Abstinence was not required but encouraged. The patients attended visits weekly during the first month, and then at 3 and at 6 months. Outcome measures were Alcohol Use Disorders Identification Test (AUDIT), Obsessive Compulsive Drinking Scale (OCDS) and Drinking Diary. The completion rate was high in both groups, especially among the patients who had been abstinent at the beginning of the study. However, among those patients who were not abstinent at baseline, 47% in both groups discontinued the study. Numbers of abstinent days were high in both groups throughout the study. Alcohol consumption measured by the AUDIT QF (quantity-frequency) score was significantly reduced in both groups, as was the craving for alcohol measured by the OCDS. Early age at first alcohol intoxication predicted poor treatment outcomes in patients treated with escitalopram, and the same was seen with the early onset of the first depressive episode. The same predictive effects were not found in patients treated with memantine. Our results indicate that both memantine and escitalopram are useful adjunct medications for the treatment of alcohol dependence co-morbid with major depression. Memantine was at least as effective with regard to

  20. Assessing the synergy between cholinomimetics and memantine as augmentation therapy in cognitive impairment in schizophrenia. A virtual human patient trial using quantitative systems pharmacology.

    Science.gov (United States)

    Geerts, Hugo; Roberts, Patrick; Spiros, Athan

    2015-01-01

    While many drug discovery research programs aim to develop highly selective clinical candidates, their clinical success is limited because of the complex non-linear interactions of human brain neuronal circuits. Therefore, a rational approach for identifying appropriate synergistic multipharmacology and validating optimal target combinations is desperately needed. A mechanism-based Quantitative Systems Pharmacology (QSP) computer-based modeling platform that combines biophysically realistic preclinical neurophysiology and neuropharmacology with clinical information is a possible solution. This paper reports the application of such a model for Cognitive Impairment In Schizophrenia (CIAS), where the cholinomimetics galantamine and donepezil are combined with memantine and with different antipsychotics and smoking in a virtual human patient experiment. The results suggest that cholinomimetics added to antipsychotics have a modest effect on cognition in CIAS in non-smoking patients with haloperidol and risperidone and to a lesser extent with olanzapine and aripiprazole. Smoking reduces the effect of cholinomimetics with aripiprazole and olanzapine, but enhances the effect in haloperidol and risperidone. Adding memantine to antipsychotics improves cognition except with quetiapine, an effect enhanced with smoking. Combining cholinomimetics, antipsychotics and memantine in general shows an additive effect, except for a negative interaction with aripiprazole and quetiapine and a synergistic effect with olanzapine and haloperidol in non-smokers and haloperidol in smokers. The complex interaction of cholinomimetics with memantine, antipsychotics and smoking can be quantitatively studied using mechanism-based advanced computer modeling. QSP modeling of virtual human patients can possibly generate useful insights on the non-linear interactions of multipharmacology drugs and support complex CNS R&D projects in cognition in search of synergistic polypharmacy.

  1. Administration of memantine during ethanol withdrawal in neonatal rats: effects on long-term ethanol-induced motor incoordination and cerebellar Purkinje cell loss.

    Science.gov (United States)

    Idrus, Nirelia M; McGough, Nancy N H; Riley, Edward P; Thomas, Jennifer D

    2011-02-01

    Alcohol consumption during pregnancy can damage the developing fetus, illustrated by central nervous system dysfunction and deficits in motor and cognitive abilities. Binge drinking has been associated with an increased risk of fetal alcohol spectrum disorders, likely due to increased episodes of ethanol withdrawal. We hypothesized that overactivity of the N-methyl-D-aspartate (NMDA) receptor during ethanol withdrawal leads to excitotoxic cell death in the developing brain. Consistent with this, administration of NMDA receptor antagonists (e.g., MK-801) during withdrawal can attenuate ethanol's teratogenic effects. The aim of this study was to determine whether administration of memantine, an NMDA receptor antagonist, during ethanol withdrawal could effectively attenuate ethanol-related deficits, without the adverse side effects associated with other NMDA receptor antagonists. Sprague-Dawley pups were exposed to 6.0 g/kg ethanol or isocaloric maltose solution via intubation on postnatal day 6, a period of brain development equivalent to a portion of the 3rd trimester. Twenty-four and 36 hours after ethanol, subjects were injected with 0, 10, or 15 mg/kg memantine, totaling doses of 0, 20, or 30 mg/kg. Motor coordination was tested on a parallel bar task and the total number of cerebellar Purkinje cells was estimated using unbiased stereology. Alcohol exposure induced significant parallel bar motor incoordination and reduced Purkinje cell number. Memantine administration significantly attenuated both ethanol-associated motor deficits and cerebellar cell loss in a dose-dependent manner. Memantine was neuroprotective when administered during ethanol withdrawal. These data provide further support that ethanol withdrawal contributes to fetal alcohol spectrum disorders. Copyright © 2010 by the Research Society on Alcoholism.

  2. A novel once-daily fixed-dose combination of memantine extended release and donepezil for the treatment of moderate to severe Alzheimer's disease: two phase I studies in healthy volunteers.

    Science.gov (United States)

    Boinpally, Ramesh; Chen, Laishun; Zukin, Stephen R; McClure, Natalie; Hofbauer, Robert K; Periclou, Antonia

    2015-07-01

    Combining two standard-of-care medications for Alzheimer's disease (AD) into a single once-daily dosage unit may improve treatment adherence, facilitate drug administration, and reduce caregiver burden. A new fixed-dose combination (FDC) capsule containing 28 mg memantine extended release (ER) and 10 mg donepezil was evaluated for bioequivalence with co-administered commercially available memantine ER and donepezil, and for bioavailability with regard to food intake. Two phase I, single-dose, randomized, open-label, crossover studies were conducted in 18- to 45-year-old healthy individuals. In MDX-PK-104 study, fasting participants (N = 38) received co-administered memantine ER and donepezil or the FDC. In MDX-PK-105 study, participants (N = 36) received three treatments: intact FDC taken while fasting or after a high-fat meal, or FDC contents sprinkled on applesauce while fasting. Standard pharmacokinetic parameters for memantine and donepezil were calculated from the plasma concentration time-curve using non-compartmental analyses. Linear mixed-effects models were used to compare: (a) FDC versus co-administered individual drugs; (b) FDC fasted versus with food; and (c) FDC sprinkled on applesauce versus FDC intact, both fasted. Safety parameters were also evaluated. The FDC capsule was bioequivalent to co-administered memantine ER and donepezil. There was no significant food effect on the bioavailability of the FDC components. There were no clinically relevant differences in time to maximum plasma concentration or safety profiles across treatments. An FDC capsule containing 28 mg memantine ER and 10 mg donepezil is bioequivalent to commercially available memantine ER and donepezil, and bioavailability is not affected by food intake or sprinkling of capsule contents on applesauce.

  3. Alzheimer's disease - input of vitamin D with mEmantine assay (AD-IDEA trial: study protocol for a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Gautier Jennifer

    2011-10-01

    Full Text Available Abstract Background Current treatments for Alzheimer's disease and related disorders (ADRD are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine. Methods The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20, hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] Discussion The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD. Trial Registration ClinicalTrials.gov number, NCT01409694

  4. Thermodynamically stable amyloid-β monomers have much lower membrane affinity than the small oligomers

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    Bidyut eSarkar

    2013-04-01

    Full Text Available Amyloid beta (Aβ is an extracellular 39-43 residue long peptide present in the mammalian cerebrospinal fluid, whose aggregation is associated with Alzheimer’s disease. Small oligomers of Aβ are currently thought to be the key to toxicity. However, it is not clear why the monomers of Aβ are non-toxic, and at what stage of aggregation toxicity emerges. Interactions of Aβ with cell membranes is thought to be the initiator of toxicity, but membrane-binding studies with different preparations of monomers and oligomers have not settled this issue. We have earlier found that thermodynamically stable Aβ monomers emerge spontaneously from oligomeric mixtures upon long term incubation in physiological solutions (Nag et al, JBC, 2011. Here we show that the membrane-affinity of these stable Aβ monomers is much lower than that of a mixture of small oligomers (containing dimers to decamers, providing a clue to the emergence of toxicity. Fluorescently labeled Aβ40 monomers show negligible binding to cell membranes of a neuronal cell line (RN46A at physiological concentrations (250 nM, while oligomers at the same concentrations show strong binding within 30 minutes of incubation. The increased affinity most likely does not require any specific neuronal receptor, since this difference in membrane-affinity was also observed in a somatic cell-line (HEK 293T. Similar results are also obtained for Aβ42 monomers and oligomers. Minimal amount of cell death is observed at these concentrations even after 36 hours of incubation. It is likely that membrane binding precedes subsequent slower toxic events induced by Aβ. Our results a provide an explanation for the non-toxic nature of Aβ monomers, b suggest that Aβ toxicity emerges at the initial oligomeric phase, and c provide a quick assay for monitoring the benign-to-toxic transformation of Aβ.

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

    Directory of Open Access Journals (Sweden)

    Rasha Mohamed Hussein

    2015-07-01

    Full Text Available 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 disease amelioration. We recently found that DNAJB6, a member of DNAJ family of heat shock proteins, effectively prevented the aggregation of short aggregation-prone peptides containing large poly glutamines (associated with CAG repeat diseases both in vitro and in cells. Moreover, recent in vitro data showed that DNAJB6 can delay the aggregation of Aβ42 peptides. In this study, we investigated the ability of DNAJB6 to prevent the aggregation of extracellular and intracellular Aβ peptides using transfection of HEK293 cells with Aβ-GFP fusion construct and performing western blotting and immunofluorescence techniques. We found that DNAJB6 indeed suppresses Aβ-GFP aggregation, but not seeded aggregation initiated by extracellular Aβ peptides. Unexpectedly and unlike what we found for peptide-mediated aggregation, DNAJB6 required interaction with HSP70 to prevent the aggregation of the Aβ-GFP fusion protein and its J-domain was crucial for its anti-aggregation effect. In addition, other DNAJ proteins as well as HSPA1a overexpression also suppressed Aβ-GFP aggregation efficiently. Our findings suggest that Aβ aggregation differs from poly Q peptide induced aggregation in terms of chaperone handling and sheds doubt on the usage of Aβ-GFP fusion construct for studying Aβ peptide aggregation in cells.

  6. Alterations in expression of Cat-315 epitope of perineuronal nets during normal ageing, and its modulation by an open-channel NMDA receptor blocker, memantine.

    Science.gov (United States)

    Yamada, Jun; Ohgomori, Tomohiro; Jinno, Shozo

    2017-06-15

    The perineuronal net (PNN), a specialized aggregate of the extracellular matrix, is involved in neuroprotection against oxidative stress, which is now recognized as a major contributor to age-related decline in brain functions. In this study, we investigated the age-related molecular changes of PNNs using monoclonal antibody Cat-315, which recognizes human natural killer-1 (HNK-1) glycan on aggrecan-based PNNs. Western blot analysis showed that the expression levels of Cat-315 epitope in the hippocampus were higher in middle-aged (MA, 12-month-old) mice than in young adult (YA, 2-month-old) mice. Although there were no differences in the expression levels of Cat-315 epitope between old age (OA, 20-month-old) and MA mice, Cat-315 immunoreactivity was also detected in astrocytes of OA mice. To focus on Cat-315 epitope in PNNs, we used YA and MA mice in the following experiments. Optical disector analysis showed that there were no differences in the numbers of Cat-315-positive (Cat-315 + ) PNNs between YA and MA mice. Fluorescence intensity analysis indicated that Cat-315 immunoreactivity in PNNs increased with age in the dorsal hippocampus, which is mainly involved in cognitive functions. Administration of an open-channel blocker of NMDA receptor, memantine, reduced the expression levels of Cat-315 epitope in the hippocampus. Furthermore, the numbers of glutamatergic and GABAergic terminals colocalized with Cat-315 epitope around parvalbumin-positive neurons were decreased by memantine. These findings provide novel insight into the involvement of PNNs in normal brain ageing, and suggest that memantine may counteract the age-related alterations in expression levels of Cat-315 epitope via regulation of its subcellular localization. © 2017 Wiley Periodicals, Inc.

  7. Low-dose memantine induced working memory improvement in the allothetic place avoidance alternation task (APAAT in young adult male rats.

    Directory of Open Access Journals (Sweden)

    Malgorzata Julita Wesierska

    2013-12-01

    Full Text Available N-methyl-D-aspartate receptors (NMDAR are involved in neuronal plasticity. To assess their role simultaneously in spatial working memory and non-cognitive learning, we used NMDAR antagonists and the Allothetic Place Avoidance Alternation Task (APAAT. In this test rats should avoid entering a place where shocks were presented on a rotating arena which requires cognitive coordination for the segregation of stimuli. The experiment took place 30 min after intraperitoneal injection of memantine (5; 10; 20 mg/kg b.w.: MemL, MemM, MemH respectively and (+MK-801 (0.1; 0.2; 0.3 mg/kg b.w.: MK-801L, MK-801M, MK-801H respectively. Rats from the control group were intact or injected with saline (0.2 ml/kg. Over three consecutive days the rats underwent habituation, two avoidance training intervals with shocks, and a retrieval test. The shock sector was alternated daily. The after-effects of the agents were tested on Day21. Rats treated with low dose memantine presented a longer maximum time avoided and fewer entrances than the MemH, MK-801M, MK-801H and Control rats. The shocks per entrances ratio, used as an index of cognitive skill learning, showed skill improvement after D1, except for rats treated by high doses of the agents. The activity levels, indicated by the distance walked, were higher for the groups treated with high doses of the agents. On D21 the MK801H rats performed the memory task better than the MemH rats, whereas the rats’ activity depended on condition, not on the group factor. These results suggest that in naïve rats mild NMDAR blockade by low-dose memantine improves working memory related to a highly challenging task.

  8. MK-801 and memantine act differently on short-term memory tested with different time-intervals in the Morris water maze test.

    Science.gov (United States)

    Duda, Weronika; Wesierska, Malgorzata; Ostaszewski, Pawel; Vales, Karel; Nekovarova, Tereza; Stuchlik, Ales

    2016-09-15

    N-methyl-d-aspartate receptors (NMDARs) play a crucial role in spatial memory formation. In neuropharmacological studies their functioning strongly depends on testing conditions and the dosage of NMDAR antagonists. The aim of this study was to assess the immediate effects of NMDAR block by (+)MK-801 or memantine on short-term allothetic memory. Memory was tested in a working memory version of the Morris water maze test. In our version of the test, rats underwent one day of training with 8 trials, and then three experimental days when rats were injected intraperitoneally with low- 5 (MeL), high - 20 (MeH) mg/kg memantine, 0.1mg/kg MK-801 or 1ml/kg saline (SAL) 30min before testing, for three consecutive days. On each experimental day there was just one acquisition and one test trial, with an inter-trial interval of 5 or 15min. During training the hidden platform was relocated after each trial and during the experiment after each day. The follow-up effect was assessed on day 9. Intact rats improved their spatial memory across the one training day. With a 5min interval MeH rats had longer latency then all rats during retrieval. With a 15min interval the MeH rats presented worse working memory measured as retrieval minus acquisition trial for path than SAL and MeL and for latency than MeL rats. MK-801 rats had longer latency than SAL during retrieval. Thus, the high dose of memantine, contrary to low dose of MK-801 disrupts short-term memory independent on the time interval between acquisition and retrieval. This shows that short-term memory tested in a working memory version of water maze is sensitive to several parameters: i.e., NMDA receptor antagonist type, dosage and the time interval between learning and testing. Copyright © 2016. Published by Elsevier B.V.

  9. Memantine (a N-Methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain after amputation or surgery: A randomised, double-blinded, crossover study

    DEFF Research Database (Denmark)

    Nikolajsen, Lone; Gottrup, Hanne; Kristensen, Anders Due

    2000-01-01

    Evidence has accumulated that the N:-methyl-D-aspartate receptor system plays a role in continuous and particularly, in stimulus-evoked pain after nerve injury. We examined, in a randomized, double-blinded, cross-over fashion, the analgesic effect of memantine (a N:-methyl-D-aspartate receptor...... to 20 mg/d. Pain was recorded daily, with the use of a 0-10 numeric rating scale. Before and at the end of each treatment period, pain and sensitivity were also assessed by using the McGill Pain Questionnaire, allodynia to touch, brush and cold, wind-up-like pain, and thresholds to mechanical stimuli...

  10. The Efficacy of Licensed-Indication Use of Donepezil and Memantine Monotherapies for Treating Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease: Systematic Review and Meta-Analysis

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    I.A. Lockhart

    2011-07-01

    Full Text Available Background/Aims: Behavioural and psychological symptoms of dementia (BPSD in Alzheimer’s disease (AD greatly increase caregiver burden. The abilities of donepezil and memantine to manage BPSD within their licensed indications in AD were compared. Methods: A systematic review, random effects meta-analysis and Bucher indirect comparison were conducted. Results: Six randomised controlled studies (4 donepezil and 2 memantine reported use within the licensed indication and had Neuropsychiatric Inventory (NPI data suitable for meta-analysis. BPSD showed significant improvement with donepezil compared with placebo [weighted mean difference (WMD in NPI –3.51, 95% confidence interval (CI –5.75, –1.27], whereas this was not the case for memantine (WMD –1.65, 95% CI –4.78, 1.49. WMD in NPI for donepezil versus memantine favoured donepezil but was not statistically significant (–1.86, 95% CI –5.71, 1.99; p = 0.34. Conclusion: Within its licensed indication, donepezil is efficacious for the management of BPSD in AD compared with placebo.

  11. Iron and aluminum interaction with amyloid-beta peptides associated with Alzheimer’s disease

    Energy Technology Data Exchange (ETDEWEB)

    Drochioiu, Gabi; Ion, Laura [Alexandru Ioan Cuza University of Iasi, 11 Carol I, Iasi 700506 (Romania); Murariu, Manuela; Habasescu, Laura [Petru Poni Institute of Macromolecular Chemistry, 41A Grigore Ghica Voda Alley, Iasi 700487 (Romania)

    2014-10-06

    An elevation in the concentration of heavy metal ions in Alzheimer’s disease (AD) brain has been demonstrated in many studies. Aβ precipitation and toxicity in AD brains seem to be caused by abnormal interactions with neocortical metal ions, especially iron, copper, zinc, and aluminum [1–3]. There is increasing evidence that iron and aluminum ions are involved in the mechanisms that underlie the neurodegenerative diseases [4,5]. However, evidence was brought to demonstrate that some Aβ fragments, at physiological pH, are not able to form binary complexes with Fe(III) ions of sufficient stability to compete with metal hydroxide precipitation [6]. On the contrary, multiple metal ions are known to interact with Aβ peptides [7]. Consequently, we investigated here the interaction of Fe(II/III) and Al(III) ions with some amyloid-β peptides and fragments that results in peptide aggregation and fibrillation [8,9]. Infrared spectroscopy, atomic force microscopy, scanning electron microscopy, electrophoresis and mass spectrometry demonstrated conformational changes of peptides in the presence of such metals.

  12. Recombinant amyloid beta-peptide production by coexpression with an affibody ligand

    Science.gov (United States)

    Macao, Bertil; Hoyer, Wolfgang; Sandberg, Anders; Brorsson, Ann-Christin; Dobson, Christopher M; Härd, Torleif

    2008-01-01

    Background Oligomeric and fibrillar aggregates of the amyloid β-peptide (Aβ) have been implicated in the pathogenesis of Alzheimer's disease (AD). The characterization of Aβ assemblies is essential for the elucidation of the mechanisms of Aβ neurotoxicity, but requires large quantities of pure peptide. Here we describe a novel approach to the recombinant production of Aβ. The method is based on the coexpression of the affibody protein ZAβ3, a selected affinity ligand derived from the Z domain three-helix bundle scaffold. ZAβ3 binds to the amyloidogenic central and C-terminal part of Aβ with nanomolar affinity and consequently inhibits aggregation. Results Coexpression of ZAβ3 affords the overexpression of both major Aβ isoforms, Aβ(1–40) and Aβ(1–42), yielding 4 or 3 mg, respectively, of pure 15N-labeled peptide per liter of culture. The method does not rely on a protein-fusion or -tag and thus does not require a cleavage reaction. The purified peptides were characterized by NMR, circular dichroism, SDS-PAGE and size exclusion chromatography, and their aggregation propensities were assessed by thioflavin T fluorescence and electron microscopy. The data coincide with those reported previously for monomeric, largely unstructured Aβ. ZAβ3 coexpression moreover permits the recombinant production of Aβ(1–42) carrying the Arctic (E22G) mutation, which causes early onset familial AD. Aβ(1–42)E22G is obtained in predominantly monomeric form and suitable, e.g., for NMR studies. Conclusion The coexpression of an engineered aggregation-inhibiting binding protein offers a novel route to the recombinant production of amyloidogenic Aβ peptides that can be advantageously employed to study the molecular basis of AD. The presented expression system is the first for which expression and purification of the aggregation-prone Arctic variant (E22G) of Aβ(1–42) is reported. PMID:18973685

  13. Recombinant amyloid beta-peptide production by coexpression with an affibody ligand

    Directory of Open Access Journals (Sweden)

    Dobson Christopher M

    2008-10-01

    Full Text Available Abstract Background Oligomeric and fibrillar aggregates of the amyloid β-peptide (Aβ have been implicated in the pathogenesis of Alzheimer's disease (AD. The characterization of Aβ assemblies is essential for the elucidation of the mechanisms of Aβ neurotoxicity, but requires large quantities of pure peptide. Here we describe a novel approach to the recombinant production of Aβ. The method is based on the coexpression of the affibody protein ZAβ3, a selected affinity ligand derived from the Z domain three-helix bundle scaffold. ZAβ3 binds to the amyloidogenic central and C-terminal part of Aβ with nanomolar affinity and consequently inhibits aggregation. Results Coexpression of ZAβ3 affords the overexpression of both major Aβ isoforms, Aβ(1–40 and Aβ(1–42, yielding 4 or 3 mg, respectively, of pure 15N-labeled peptide per liter of culture. The method does not rely on a protein-fusion or -tag and thus does not require a cleavage reaction. The purified peptides were characterized by NMR, circular dichroism, SDS-PAGE and size exclusion chromatography, and their aggregation propensities were assessed by thioflavin T fluorescence and electron microscopy. The data coincide with those reported previously for monomeric, largely unstructured Aβ. ZAβ3 coexpression moreover permits the recombinant production of Aβ(1–42 carrying the Arctic (E22G mutation, which causes early onset familial AD. Aβ(1–42E22G is obtained in predominantly monomeric form and suitable, e.g., for NMR studies. Conclusion The coexpression of an engineered aggregation-inhibiting binding protein offers a novel route to the recombinant production of amyloidogenic Aβ peptides that can be advantageously employed to study the molecular basis of AD. The presented expression system is the first for which expression and purification of the aggregation-prone Arctic variant (E22G of Aβ(1–42 is reported.

  14. Spatial patterns of brain amyloid-beta burden and atrophy rate associations in mild cognitive impairment

    NARCIS (Netherlands)

    Tosun, Duygu; Schuff, Norbert; Mathis, Chester A.; Jagust, William; Weiner, Michael W.; Saradha, A.; Abdi, Herve; Abdulkadir, Ahmed; Abeliovich, Asa; Abellan van Kan, Gabor; Abner, Erin; Acharya, Deepa; Agrusti, Antonella; Agyemang, Alex; Ahdidan, Jamila; Ahmed, Shiek; Ahn, Jae Eun; Aisen, Paul; Aksu, Yaman; Al-Akhras, Mousa; Alarcon, Marcelo; Alberca, Roman; Alexander, Gene; Alexander, Daniel; Alin, Aylin; Almeida, Fabio; Amlien, Inge; Anand, Shyam; Anderson, Dallas; Andrew, Marilee; Angersbach, Steve; Anjum, Ayesha; Aoyama, Eiji; Arfanakis, Konstantinos; Armor, Tom; Arnold, Steven; Arunagiri, Vidhya; Asatryan, Albert; Ashe-McNalley, Cody; Ashiga, Hirokazu; Assareh, Arezoo; Le Page, Aurelie; Avants, Brian; Avinash, Gopal; Aviv, Richard; Awasthi, Sukrati; Ayan-Oshodi, Mosun; Babic, Tomislav; Baek, Young; Bagci, Ulas; Bai, Shuyang; Baird, Geoffrey; Baker, John; Banks, Sarah; Bard, Jonathan; Barnes, Josephine; Bartlett, Jonathan; Bartzokis, George; Barua, Neil; Bauer, Corinna; Bayley, Peter; Beck, Irene; Becker, James; Becker, J. Alex; Beckett, Laurel; Bednar, Martin; Beg, Mirza Faisal; Bek, Stephan; Belaroussi, Boubakeur; Belmokhtar, Nabil; Bernard, Charlotte; Bertram, Lars; Bhaskar, Uday; Biffi, Alessandro; Bigler, Erin; Bilgic, Basar; Bishop, Courtney; Bittner, Daniel; Black, Ronald; Bogorodzki, Piotr; Bokde, Arun; Bonner-Jackson, Aaron; Boppana, Madhu; Bourgeat, Pierrick; Bowes, Mike; Bowman, DuBois; Bowman, Gene; Braskie, Meredith; Braunewell, Karl; Breitner, Joihn; Bresell, Anders; Brewer, James; Brickman, Adam; Britschgi, Markus; Broadbent, Steve; Brogren, Jacob; Brooks, David; Browndyke, Jeffrey; Brunton, Simon; Buchert, Ralph; Buchsbaum, Monte; Buckley, Chris; Buerger, Katharina; Burger, Cyrill; Burnham, Samantha; Burns, Jeffrey; Burton, David; Butman, John; Cabeza, Rafael; Cairns, Nigel; Callhoff, Johanna; Calvini, Piero; Cantillon, Marc; Capella, Heraldo; Carbotti, Angela; Cardona-Sanclemente, Luis Eduardo; Carle, Adam; Carmasin, Jeremy; Carranza-Ath, Fredy; Casabianca, Jodi; Casanova, Ramon; Cash, David; Cedarbaum, Jesse; Cella, Massimo; Celsis, Pierre; Chanu, Pascal; Chao, Linda; Charil, Arnaud; Chemali, Zeina; Chen, Rong; Chen, Jake; Chen, Gennan; Chen, Wei; Chen, Kewei; Chen, Shuzhong; Chen, Minhua; Cheng, Wei-Chen; Cherkas, Yauheniya; Chertkow, Howard; Cheung, Charlton; Cheung, Vinci; Chiang, Gloria; Chiba, Koji; Chin, Simon; Chisholm, Jane; Cho, Youngsang; Choe, John; Choubey, Suresh; Chowbina, Sudhir; Christensen, Anette Luther; Clark, David; Clark, Chris; Clarkson, Matt; Clayton, David; Clunie, David; Coen, Michael; Coimbra, Alexandre; Compton, David; Coppola, Giovanni; Coulin, Samuel; Cover, Keith S.; Crane, Paul; Crans, Gerald; Croop, Robert; Crowther, Daniel; Crum, William; Cui, Yue; Curry, Charles; Curtis, Steven; Cutter, Gary; Daiello, Lori; Dake, Michael; Dale, Anders; Daliri, Mohammad Reza; Damato, Vito Domenico; Darby, Eveleen; Darkner, Sune; Davatzikos, Christos; Dave, Jay; David, Renaud; DavidPrakash, Bhaskaran; Davidson, Julie; de Bruijne, Marleen; de Meyer, Geert; de Nunzio, Giorgio; Decarli, Charles; Dechairo, Bryan; DeDuck, Kristina; Dehghan, Hossein; Dejkam, Arsalan; Delfino, Manuel; Della Rosa, Pasquale Anthony; Dellavedova, Luca; Delpassand, Ebrahim; Delrieu, Julien; DeOrchis, Vincent; Depy Carron, Delphine; deToledo-Morrell, Leyla; Devanand, Davangere; Devanarayan, Viswanath; DeVous, Michael; Diaz-Arrastia, Ramon; Bradford, Dickerson; Ding, Xiaobo; Dinov, Ivo; Dobson, Howard; Dodge, Hiroko; Donohue, Michael; Dore, Vincent; Dorflinger, Ernest; Dowling, Maritza; Duan, Xujun; Dubal, Dena; Duchesne, Simon; Duff, Kevin; Dukart, Jrgen; Durazzo, Timothy; Dykstra, Kevin; Earl, Nancy; Edula, Goutham; Ekin, Ahmet; Elcoroaristizabal, Xabier; Emahazion, Tesfai; Engelman, Corinne; Epstein, Noam; Erten-Lyons, Deniz; Eskildsen, Simon; Falcone, Guido; Fan, Lingzhong; Fan, Yong; Farahibozorg, Seyedehrezvan; Farb, Norman; Farnum, Michael; Farrer, Lindsay; Farzan, Ali; Faux, Noel; Feldman, Betsy; Feldman, Howard; Feldman, Susan; Fennema-Notestine, Christine; Fernandes, Michel; Fernandez, Elsa; Ferrarini, Luca; Ferreira, Manuel Joao; Ferrer, Eugene; Figurski, Michal; Filipovych, Roman; Fillit, Howard; Finch, Stephen; Finlay, Daniel; Fiot, Jean-Baptiste; Flenniken, Derek; Fletcher, P. Thomas; Fletcher, Evan; Flynn Longmire, Crystal; Focke, Niels; Forman, Mark; Forsythe, Alan; Fox, Steven; Fox-Bosetti, Sabrina; Francis, Alexander L.; Franco-Villalobos, Conrado; Franko, Edit; Freeman, Stefanie; Friedrich, Christoph M.; Friesenhahn, Michel; Frings, Lars; Frisoni, Giovanni; Fritzsche, Klaus; Fujimoto, Yoko; Fujiwara, Ken; Fullerton, Terence; Furney, Simon; Gallins, Paul; Galvin, Ben; Gamst, Anthony; Gan, Ke; Garcia, Maria Teresa; Garg, Gaurav; Gaser, Christian; Gastineau, Edward; Gauthier, Serge; Gavett, Brandon; Gavidia, Giovana; Gazdzinski, Stefan; Ge, Qi; Ge, Tian; Gemme, Gianluca; Geraci, Joseph; Ghassabi, Zeinab; Gieschke, Ronald; Gil, Juan E.; Gill, Ryan; Gitelman, Darren; Gleason, Carey; Glymour, M. Maria; Godbey, Michael; Goghari, Vina; Gold, Michael; Goldberg, Terry; Goldman, Jennifer; Gomeni, Roberto; Gong, Shangwenyan; Gonzales, Celedon; Goodro, Robert; Gordon, Brian; Gore, Chris; Gorriz, Juan Manuel; Grachev, Igor; Grandey, Emily; Grasela, Thaddeus; Gratt, Jeremy; Gray, Katherine; Greenberg, Barry; Gregg, Keith; Gregory, Erik; Greicius, Michael; Greve, Douglas; Grill, Joshua; Gross, Alden; Gross, Alan; Guignot, Isabelle; Guo, Jeffrey; Guo, Qimiao; Guo, Hongbin; Guo, Lianghao; Habeck, Christian; Hai, Yizhen; Haight, Thaddeus; Hammarstrom, Per; Hampel, Harald; Han, Duke; Han, Jian; Han, Tony; Hanif, Muhammad; Hanna, Yousef; Hardy, Peter; Harvey, Danielle; Hasan, Md Kamrul; Hayashi, Toshihiro; Hazart, Aurelien; He, Huiguang; He, Yong; Head, Denise; Heckemann, Rolf; Heidebrink, Judith; Henderson, David; Henrard, Sebastien; Herholz, Karl; Hernandez, Monica; Herskovits, A. Zara; Hess, Christopher; Hildenbrand, Maike; Hobart, Jeremy; Hoffman, John; Holder, Daniel; Hollingworth, Paul; Holmes, Robin; Honigberg, Lee; Hoppin, Jack; Hou, Yangyang; Hsu, Ailing; Hsu, Wei-Wen; Hu, Xiaolan; Hu, Zhiwei; Hu, William; Huang, Juebin; Huang, Chien-Chih; Huang, Chingwen; Huang, Shuai; Huang, Yifan; Huang, Fude; Huang, Chun-Jung; Huang, Shu-Pang; Hubbard, Rebecca; Huentelman, Matthew; Hui, Shen; Huppertz, Hans-Jürgen; Hurko, Orest; Hurt, Stephen; Huyck, Susan; Hwang, Scott; Hyun, JungMoon; Ifeachor, Emmanuel; Iglesias, Martina; Ikari, Yasuhiko; Ikonomidou, Vasiliki; Imani, Farzin; Immermann, Fred; Inlow, Mark; Inoue, Lurdes; Insel, Philip; Irizarry, Michael; Irungu, Benson mwangi; Ishibashi, Taro; Ishii, Kenji; Ismail, Sara; Ismail, Shahina; Ito, Kaori; Iturria-Medina, Yasser; Iwatsubo, Takeshi; Jacobson, Mark; Jacqmin, Philippe; Jafari, Aria; Jafari-Khouzani, Kourosh; Jaffe, Carl; Jara, Hernan; Jasperse, Bas; Jedynak, Bruno; Jefferson, Angela; Jennings, J. Richard; Jessen, Walter; Jia, Fucang; Jiang, Tianzi; Jing, Huang; Johnson, Julene; Johnson, Sterling; Johnson, David K.; Jones, Richard; Juengling, Freimut; Juh, Rahyeong; Julin, Per; Kadish, Bill; Kahle-Wrobleski, Kristin; Kallam, Hanimi Reddy; Kamboh, M. Ilyas; Kaneko, Tomoki; Kaneta, Tomohiro; Kang, Ju Hee; Karageorgiou, Elissaios; Karantzoulis, Stella; Karlawish, Jason; Katz, Elyse; Kaushik, Sandeep S.; Kauwe, John; Kawakami, Hirofumi; Kazimipoor, Borhan; Kelleher, Thomas; Kennedy, Richard; Kerchner, Geoffrey; Kerrouche, Nacer; Khalil, Iya; Khalil, Andre; Killeen, Neil; Killiany, Ron; Kim, Jong Hun; Kim, Heeyoung; Kim, Ana; Kim, Yeonhee; Kim, Hyoungkyu; Kim, Seongkyun; Kim, Hyewon; Kimberg, Daniel; Kimura, Tokunori; King, Richard; Kirby, Justin; Kirsch, Wolff; Klimas, Michael; Kline, Richard; Kling, Mitchel; Klopfenstein, Erin; Koikkalainen, Juha; Kokomoor, Anders; Kolasny, Anthony; Koppel, Jeremy; Korolev, Igor; Kotran, Nickolas; Kouassi, Alex; Kowalczyk, Adam; Kozma, Lynn; Krams, Michael; Kratzer, Martina; Kuceyeski, Amy; Kuhn, Felix Pierre; Kumar, Sreedhar; Kuo, Hsun Ting; Kuo, Julie; Kurosawa, Ken; Kwon, Oh Hun; Labrish, Catherine; Laforet, Genevieve; Lai, Song; Lakatos, Anita; Lam, On Ki; Lampron, Antoine; Landau, Susan; Landen, Jaren; Lane, Richard; Langbaum, Jessica; Langford, Dianne; Lanius, Vivian; Laxamana, Joel; Le, Trung; Leahy, Richard; Lee, Jong-Min; Lee, Vita; Lee, Joseph H.; Lee, Grace; Lee, Dongsoo; Lee, Noah; Lefkimmiatis, Stamatis; Lemaitre, Herve; Lenfant, Pierre; Lenz, Robert; Leoutsakos, Jeannie-Marie; Lester, Gayle; Levey, Allan; Li, Shi-jiang; Li, Shanshan; Li, Wenjun; Li, Chin-Shang; Li, Xiaodong; Li, Rui; Li, Ming; Li, Lexin; Li, Jinhe; Li, Yi; Li, Quanzheng; Li, Gang; Liang, Kuchang; Liang, Peipeng; Liang, Lichen; Liao, Yuan-Lin; Lin, Ling-chih; Lin, Lan; Lin, Mingkuan; Lin, Ai-Ling; Liu, Songling; Liu, Yuan; Liu, Tianming; Liu, Meijie; Liu, Xiuwen; Liu, Li; Liu, Honggang; Liu, Pu; Liu, Tao; Liu, Sophia; Liu, Dazhong; Lo, Raymond; Lobanov, Victor; Loewenstein, David; Logovinsky, Veronika; Long, Xiaojing; Long, Ziyi; Looi, Jeffrey; Lu, Po-Haong; Lukic, Ana; Lull, Juan J.; Luo, Xiongjian; Lynch, John; Ma, Lei; Mackin, Scott; Mada, Marius; Magda, Sebastian; Maglio, Silvio; Maikusa, Norihide; Mak, Henry Ka-Fung; Malave, Vicente; Maldjian, Joseph; Mandal, Pravat; Mangin, Jean-Francois; Manjon, Jose; Mantri, Ninad; Manzour, Amir; Marambaud, Philippe; Marchewka, Artur; Marek, Kenneth; Markind, Samuel; Marshall, Gad; Martinez Torteya, Antonio; Mather, Mara; Mathis, Chester; Matoug, Sofia; Matsuo, Yoshiyuki; Mattei, Peter; Matthews, Dawn; McArdle, John; McCarroll, Steven; McEvoy, Linda; McGeown, William; McGonigle, John; McIntyre, John; McLaren, Donald; McQuail, Joseph; Meadowcroft, Mark; Meda, Shashwath; Mehta, Nirav; Melie-Garcia, Lester; Melrose, Rebecca; Mendonca, Brian; Menendez, Manuel; Meredith, Jere; Merrill, David; Mesulam, Marek-Marsel; Metti, Andrea; Meyer, Carsten; Mez, Jesse; Mickael, Guedj; Miftahof, Roustem; Mikhno, Arthur; Miller, David; Millikin, Colleen; Min, Ye; Mirza, Mubeena; Mistridis, Panagiota; Mitchell, Meghan; Mitsis, Effie; Mohan, Ananth; Moore, Dana; Moradi Birgani, Parmida; Moratal, David; Morimoto, Bruce; Mormino, Elizabeth; Mortamet, Benedicte; Moscato, Pablo; Mueller, Kathyrne; Mueller, Susanne; Mueller, Notger; Mukherjee, Shubhabrata; Mulder, Emma; Murayama, Shigeo; Murphy, Michael; Murray, Brian; Musiek, Erik; Myers, Amanda; Najafi, Shahla; Nazarparvar, Babak; Nazeri, Arash; Nettiksimmons, Jasmine; Neu, Scott; Ng, Yen-Bee; Nguyen, Nghi; Nguyen Xuan, Tuong; Nichols, Thomas; Nicodemus, Kristin; Niecko, Timothy; Nielsen, Casper; Notomi, Keiji; Nutakki, Gopi Chand; O'Bryant, Sid; O'Neil, Alison; Obisesan, Thomas; Oh, Dong Hoon; Oh, Joonmi; Okonkwo, Ozioma; Olde Rikkert, Marcel; Olmos, Salvador; Ortner, Marion; Ostrowitzki, Susanne; Oswald, Annahita; Ott, Brian; Ourselin, Sebastien; Ouyang, Gaoxiang; Paiva, Renata; Pan, Zhifang; Pande, Yogesh; Pardo, Jose; Pardoe, Heath; Park, Hyunjin; Park, Lovingly; Park, Moon Ho; Park, Sang hyun; Park, Kee Hyung; Park, Sujin; Parsey, Ramin; Parveen, Riswana; Paskavitz, James; Patel, Yogen; Patil, Manasi; Pawlak, Mikolaj; Payoux, Pierre; Pearson, Jim; Peavy, Guerry; Pell, Gaby; Peng, Yahong; Pennec, Xavier; Pepin, Jean louis; Perea, Rodrigo; Perneczky, Robert; Petitti, Diana; Petrella, Jeffrey; Peyrat, Jean-Marc; Pezoa, Jorge; Pham, Chi-Tuan; Phillips, Justin; Phillips, Nicole; Pierson, Ronald; Piovezan, Mauro; Podhorski, Adam; Pollari, Mika; Pontecorvo, Michael; Poppenk, Jordan; Posner, Holly; Potkin, Steven; Potter, Guy; Potter, Elizabeth; Poulin, Stephane; Prasad, Gautam; Prenger, Kurt; Prince, Jerry; Priya, Anandh; Puchakayala, Shashidhar Reddy; Qiu, Ruolun; Qiu, Anqi; Qiu, Wendy; Qualls, Constance Dean; Rabie, Huwaida; Rajeesh, Rajeesh; Rallabandi, V. P. Subramanyam; Ramage, Amy; Randolph, Christopher; Rao, Anil; Rao, Divya; Raubertas, Richard; Ray, Debashis; Razak, Hana; Redolfi, Alberto; Reed, Bruce; Reid, Andrew; Reilhac, Anthonin; Reinsberger, Claus; Restrepo, Lucas; Retico, Alessandra; Richards, John; Riddle, William; Ries, Michele; Rincon, Mariano; Rischall, Matt; Rizk-Jackson, Angela; Robieson, Weining; Rocha-Rego, Vanessa; Rogalski, Emily; Rogers, Elizabeth; Rojas, Ignacio; Rojas Balderrama, Javier; Romero, Klaus; Rorden, Chris; Rosand, Jonathan; Rosen, Allyson; Rosen, Ori; Rosenberg, Paul; Ross, David; Roubini, Eli; Rousseau, François; Rowe, Christopher; Rubin, Daniel; Rubright, Jonathan; Ruiz, Agustin; Rusinek, Henry; Ryan, Laurie; Saad, Ahmed; Sabbagh, Marway; Sabuncu, Mert; Sachs, Michael; Sadeghi, Ali; Said, Yasmine; Saint-Aubert, Laure; Sakata, Muneyuki; Salat, David; Salmon, David; Salter, Hugh; Samwald, Matthias; Sanchez, Luciano; Sanders, Elizabeth; Sanjo, Nobuo; Sarnel, Haldun; Sato, Hajime; Sato, Shinji; Saumier, Daniel; Savio, Alexandre; Sawada, Ikuhisa; Saykin, Andrew; Schaffer, J. David; Scharre, Douglas; Schegerin, Marc; Schlosser, Gretchen; Schmand, Ben; Schmansky, Nick; Schmidt, Mark; Schmidt-Wilcke, Tobias; Schneider, Lon; Schramm, Hauke; Schuerch, Markus; Schwartz, Eben; Schwartz, Craig; Schwarz, Adam; Seethamraju, Ravi; Seixas, Flavio; Selnes, Per; Senjem, Matthew; Senlin, Wang; Seo, Sang Won; Sethuraman, Gopalan; Sevigny, Jeffrey; Sfikas, Giorgos; Sghedoni, Roberto; Shah, Said Khalid; Shahbaba, Babak; Shams, Soheil; Shattuck, David; Shaw, Leslie; Sheela, Jaba; Shen, Weijia; Shen, Qian; Shera, David; Sherman, John; Sherva, Richard; Shi, Feng; Shukla, Vinay; Shuler, Catherine; Shulman, Joshua; Siegel, Rene; Siemers, Eric; Silveira, Margarida; Silver, Michael; Silverman, Daniel; Sim, Ida; Simmons, Andy; Simoes, Rita; Simon, Melvin; Simpson, Ivor; Singh, Simer Preet; Singh, Nikhil; Siuciak, Judy; Sjogren, Niclas; Skinner, Jeannine; Skup, Martha; Small, Gary; Smith, Michael; Smith, Benjamin; Smith, Charles; Smyth, Timothy; Snow, Sarah; Soares, Holly; Soldea, Octavian; Solomon, Paul; Solomon, Alan; Som, Subhojit; Song, Changhong; Song, Mingli; Sosova, Iveta; Soudah, Eduardo; Soydemir, Melih; Spampinato, Maria Vittoria; Spenger, Christian; Sperling, Reisa; Spiegel, Rene; Spies, Lothar; Squarcia, Sandro; Squire, Larry; Staff, Roger; Stern, Yaakov; Straw, Jack; Stricker, Nikki; Strittmatter, Stephen; Stühler, Elisabeth; Styren, Scot; Subramanian, Vijayalakshmi; Sugishita, Morihiro; Sukkar, Rafid; Sun, Jia; Sun, Ying; Sun, Yu; Sundell, Karen; Suri, Muhammad; Suzuki, Akiyuki; Svetnik, Vladimir; Swan, Melanie; Takahasi, Tetsuhiko; Takeuchi, Tomoko; Tanaka, Shoji; Tanchi, Chaturaphat; Tancredi, Daniel; Tao, Wenwen; Tao, Dacheng; Taylor-Reinwald, Lisa; Teng, Edmond; Terlizzi, Rita; Thames, April; Thiele, Frank; Thomas, Benjamin; Thomas, Ronald; Thompson, Paul; Thompson, Wesley; Thornton-Wells, Tricia; Thorvaldsson, Valgeir; Thurfjell, Lennart; Titeux, Laurence; Tokuda, Takahiko; Toledo, Juan B.; Tolli, Tuomas; Toma, Ahmed; Tomita, Naoki; Toro, Roberto; Torrealdea, Patxi; Tousian, Mona; Toussaint, Paule; Toyoshiba, Hiroyoshi; Tractenberg, Rochelle E.; Trittschuh, Emily; Trojanowski, John; Truran, Diana; Tsechpenakis, Gavriil; Tucker-Drob, Elliot; Tufail, Ahsan; Tung, Joyce; Turken, And; Ueda, Yoji; Ullrich, Lauren; Umadevi Venkataraju, Kannan; Umar, Nisser; Uzunbas, Gokhan; van de Nes, Joseph; van der Brug, Marcel; van Horn, John; van Leemput, Koen; van Train, Kenneth; van Zeeland, Ashley; Vasanawala, Minal; Vemuri, Prashanthi; Verwaerde, Philippe; Videbaek, Charlotte; Vidoni, Eric; Villanueva-Meyer, Javier; Visser, Pieter Jelle; Vitolo, Ottavio; Vounou, Maria; Wade, Sara; Walhovd, Kristine B.; Wan, Hong; Wang, Huanli; Wang, Yongmei Michelle; Wang, Yalin; Wang, Angela; Wang, Lei; Wang, Yue; Wang, Xu; Wang, Ze; Wang, Yaping; Wang, Tiger; Wang, Alex; Wang, Huali; Wang, Li-San; Wang, Wei; Wang, Li; Ward, Michael; Warfield, Simon; Waring, Stephen; Watanabe, Toshiyuki; Webb, David; Wei, Lili; Weiner, Michael; Wen, Shu-Hui; Wenjing, Li; Wenzel, Fabian; Westlye, Lars T.; Whitcher, Brandon; Whitlow, Christopher; Whitwell, Jennifer; Wilhelmsen, Kirk; Williams, David; Wilmot, Beth; Wimsatt, Matt; Wingo, Thomas; Wiste, Heather; Wolfson, Tanya; Wolke, Ira; Wolz, Robin; Woo, Jongwook; Woo, Ellen; Woods, Lynn; Worth, Andrew; Worth, Eric; Wouters, Hans; Wu, Teresa; Wu, Yi-Gen; Wu, Liang; Wu, Xiaoling; Wyman, Bradley; Wyss-Coray, Tony; Xiao, Guanghua; Xiao, Liu; Xie, Sharon; Xu, Shunbin; Xu, Ye; Xu, Yi-Zheng; Xu, Guofan; Xu, Jun; Yamane, Tomohiko; Yamashita, Fumio; Yan, Yunyi; Yan, Pingkun; Yang, Eric; Yang, Jinzhong; Yang, Qing X.; Yang, Zijiang; Yang, Guang; Yang, Zhitong; Yang, Wenlu; Ye, Liang; Ye, Byoung Seok; Ye, Jieping; Ye, Jong; Yee, Laura; Yesavage, Jerome; Ying, Song; Yoo, Bongin; Young, Jonathan; Yu, Shiwei; Yu, Dongchuan; Yuan, Guihong; Yuan, Kai; Yushkevich, Paul; Zaborszky, Laszlo; Zagorodnov, Vitali; Zagorski, Michael; Zawadzki, Rezi; Zeitzer, Jamie; Zelinski, Elizabeth; Zhang, Kurt; Zhang, Huixiong; Zhang, Tianhao; Zhang, Xin; Zhang, Ping; Zhang, Bin; Zhang, Jing; Zhang, Linda; Zhang, Lijun; Zhang, Zhiguo; Zhao, Qinying; Zhao, Jim; Zhao, Peng; Zhen, Xiantong; Zheng, Yuanjie; Zhijun, Yao; Zhou, Bin; Zhou, Sheng; Zhu, Wen; Zhu, Hongtu; Zhu, Wanlin; Zilka, Samantha; Zito, Giancarlo; Zou, Heng

    2011-01-01

    Amyloid-β accumulation in the brain is thought to be one of the earliest events in Alzheimer's disease, possibly leading to synaptic dysfunction, neurodegeneration and cognitive/functional decline. The earliest detectable changes seen with neuroimaging appear to be amyloid-β accumulation detected by

  15. Amyloid-beta oligomer detection by ELISA in cerebrospinal fluid and brain tissue

    NARCIS (Netherlands)

    Bruggink, K.A.; Jongbloed, W.; Biemans, E.A.L.M.; Veerhuis, R.; Claassen, J.A.H.R.; Kuiperij, H.B.; Verbeek, M.M.

    2013-01-01

    Amyloid-β (Aβ) deposits are important pathological hallmarks of Alzheimer's disease (AD). Aβ aggregates into fibrils; however, the intermediate oligomers are believed to be the most neurotoxic species and, therefore, are of great interest as potential biomarkers. Here, we have developed an

  16. Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer's disease.

    Science.gov (United States)

    Sehlin, Dag; Fang, Xiaotian T; Cato, Linda; Antoni, Gunnar; Lannfelt, Lars; Syvänen, Stina

    2016-02-19

    Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood-brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid β (Aβ) antibody mAb158 is radiolabelled and conjugated to a transferrin receptor antibody to enable receptor-mediated transcytosis across the BBB. PET imaging of two different mouse models with Aβ pathology clearly visualize Aβ in the brain. The PET signal increases with age and correlates closely with brain Aβ levels. Thus, we demonstrate that antibody-based PET ligands can be successfully used for brain imaging.

  17. Structure-Based Peptide Design to Modulate Amyloid Beta Aggregation and Reduce Cytotoxicity.

    Directory of Open Access Journals (Sweden)

    Jitendra Kumar

    Full Text Available The deposition of Aβ peptide in the brain is the key event in Alzheimer disease progression. Therefore, the prevention of Aβ self assembly into disease-associated oligomers is a logical strategy for treatment. π stacking is known to provide structural stability to many amyloids; two phenylalanine residues within the Aβ 14-23 self recognition element are in such an arrangement in many solved structures. Therefore, we targeted this structural stacking by substituting these two phenylalanine residues with their D-enantiomers. The resulting peptides were able to modulate Aβ aggregation in vitro and reduce Aβ cytotoxicity in primary neuronal cultures. Using kinetic analysis of fibril formation, electron microscopy and dynamic light scattering characterization of oligomer size distributions, we demonstrate that, in addition to altering fibril structural characteristics, these peptides can induce the formation of larger amorphous aggregates which are protective against toxic oligomers, possibly because they are able to sequester the toxic oligomers during co-incubation. Alternatively, they may alter the surface structure of the oligomers such that they can no longer interact with cells to induce toxic pathways.

  18. alpha-Synuclein enhances secretion and toxicity of amyloid beta peptides in PC12 cells

    NARCIS (Netherlands)

    Kazmierczak, Anna; Strosznajder, Joanna B.; Adamczyk, Agata

    2008-01-01

    alpha-Synuclein is the fundamental component of Lewy bodies which occur in the brain of 60% of sporadic and familial Alzheimer's disease patients. Moreover, a proteolytic fragment of alpha-synuclein, the so-called non-amyloid component of Alzheimer's disease amyloid, was found to be an integral part

  19. Protective Effects of Indian Spice Curcumin Against Amyloid Beta in Alzheimer’s Disease

    Science.gov (United States)

    Reddy, P. Hemachandra; Manczak, Maria; Yin, Xiangling; Grady, Mary Catherine; Mitchell, Andrew; Tonk, Sahil; Kuruva, Chandra Sekhar; Bhatti, Jasvinder Singh; Kandimalla, Ramesh; Vijayan, Murali; Kumar, Subodh; Wang, Rui; Adi Pradeepkiran, Jangampalli; Ogunmokun, Gilbert; Thamarai, Kavya; Quesada, Kandi; Boles, Annette; Reddy, Arubala P

    2018-01-01

    The purpose of our article is to assess the current understanding of Indian spice ‘Curcumin’ against amyloid-β (Aβ)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, anti-oxidant, anti-arthritis, pro-healing and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on amyloid-β and curcumin has revealed that curcumin prevents amyloid-β aggregation and crosses the blood brain barrier (BBB), reach brain cells and protect neurons from various toxic insults of aging and amyloid-β in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin’s bioavailability and urgent need for new formulation to increase its brain levels to treat patients with AD. PMID:29332042

  20. Conformational stability of fibrillar amyloid-beta oligomers via protofilament pair formation - a systematic computational study.

    Directory of Open Access Journals (Sweden)

    Anna Kahler

    Full Text Available Amyloid-[Formula: see text] (A[Formula: see text] oligomers play a crucial role in Alzheimer's disease due to their neurotoxic aggregation properties. Fibrillar A[Formula: see text] oligomerization can lead to protofilaments and protofilament pairs via oligomer elongation and oligomer association, respectively. Small fibrillar oligomers adopt the protofilament topology, whereas fibrils contain at least protofilament pairs. To date, the underlying growth mechanism from oligomers to the mature fibril still remains to be elucidated. Here, we performed all-atom molecular dynamics simulations in explicit solvent on single layer-like protofilaments and fibril-like protofilament pairs of different size ranging from the tetramer to the 48-mer. We found that the initial U-shaped topology per monomer is maintained over time in all oligomers. The observed deviations of protofilaments from the starting structure increase significantly with size due to the twisting of the in-register parallel [Formula: see text]-sheets. This twist causes long protofilaments to be unstable and leads to a breakage. Protofilament pairs, which are stabilized by a hydrophobic interface, exhibit more fibril-like properties such as the overall structure and the twist angle. Thus, they can act as stable conformational templates for further fibril growth. Key properties like the twist angle, shape complementarity, and energetics show a size-dependent behavior so that small oligomers favor the protofilament topology, whereas large oligomers favor the protofilament pair topology. The region for this conformational transition is at the size of approximately twelve A[Formula: see text] monomers. From that, we propose the following growth mechanism from A[Formula: see text] oligomers to fibrils: (1 elongation of short protofilaments; (2 breakage of large protofilaments; (3 formation of short protofilament pairs; and (4 elongation of protofilament pairs.

  1. Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2

    Directory of Open Access Journals (Sweden)

    Koutaro Takamatsu

    2014-11-01

    Full Text Available The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS cell-derived macrophage-like cells for Alzheimer's disease (AD. In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aβ added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aβ. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aβ. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2, which is a protease with Aβ-degrading activity. In vitro, expression of NEP2 but not anti-Aβ scFv enhanced the effect to reduce the level of soluble Aβ oligomer in the culture medium and to alleviate the neurotoxicity of Aβ. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2 in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aβ in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.

  2. Neurotrophic and Neurotoxic Effects of Amyloid |beta Protein: Reversal by Tachykinin Neuropeptides

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    Yankner, Bruce A.; Duffy, Lawrence K.; Kirschner, Daniel A.

    1990-10-01

    The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.

  3. Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways.

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    Nafar, F; Clarke, J P; Mearow, K M

    2017-05-01

    Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Cholinergic Neurons - Keeping Check on Amyloid beta in the Cerebral Cortex

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    Saak V. Ovsepian

    2013-12-01

    Full Text Available The physiological relevance of the uptake of ligands with no apparent trophic functions via the p75 neurotrophin receptor (p75NTR remains unclear. Herein, we propose a homeostatic role for this in clearance of amyloid β (Aβ in the brain. We hypothesize that uptake of Aβ in conjunction with p75NTR followed by its degradation in lysosomes endows cholinergic basalo-cortical projections enriched in this receptor a facility for maintaining physiological levels of Aβ in target areas. Thus, in addition to the diffuse modulator influence and channeling of extra-thalamic signals, cholinergic innervations could supply the cerebral cortex with an elaborate system for Aβ drainage. Interpreting the emerging relationship of new molecular data with established role of cholinergic modulator system in regulating cortical network dynamics should provide new insights into the brain physiology and mechanisms of neuro-degenerative diseases.

  5. Amyloid beta Fibril Elongation by Monomers Involves Disorder at the Tip

    Czech Academy of Sciences Publication Activity Database

    Bacci, M.; Vymětal, Jiří; Mihajlovic, M.; Caflisch, A.; Vitalis, A.

    2017-01-01

    Roč. 13, č. 10 (2017), s. 5117-5130 ISSN 1549-9618 Institutional support: RVO:61388963 Keywords : molecular dynamics simulations * atomic resolution structure * A beta Subject RIV: CF - Physical ; Theoretical Chemistry OBOR OECD: Physical chemistry Impact factor: 5.245, year: 2016

  6. Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta.

    Science.gov (United States)

    Oikonomidi, Aikaterini; Lewczuk, Piotr; Kornhuber, Johannes; Smulders, Yvo; Linnebank, Michael; Semmler, Alexander; Popp, Julius

    2016-10-01

    Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1-42 (Aβ1-42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys-CSF), 5-methyltetrahydrofolate (5-MTHF), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1-42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5-MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1-42, and may contribute to the accumulation of amyloid pathology in the brain. Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. We found associations between CSF levels of soluble APP forms and Aβ1-42, and markers of the homocysteine metabolism in both plasma and CSF in adults with normal cognition. Disturbed homocysteine metabolism may represent a target for preventive and early disease-modifying interventions in Alzheimer's disease. © 2016 International Society for Neurochemistry.

  7. Protective Effects of Indian Spice Curcumin Against Amyloid Beta in Alzheimer’s Disease

    OpenAIRE

    Reddy, P. Hemachandra; Manczak, Maria; Yin, Xiangling; Grady, Mary Catherine; Mitchell, Andrew; Tonk, Sahil; Kuruva, Chandra Sekhar; Bhatti, Jasvinder Singh; Kandimalla, Ramesh; Vijayan, Murali; Kumar, Subodh; Wang, Rui; Adi Pradeepkiran, Jangampalli; Ogunmokun, Gilbert; Thamarai, Kavya

    2018-01-01

    The purpose of our article is to assess the current understanding of Indian spice ‘Curcumin’ against amyloid-β (Aβ)-induced toxicity in Alzheimer’s disease (AD) pathogenesis. Natural products, such as ginger, curcumin and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes and neurological disorders. Products derived from plants are known to have protective effe...

  8. 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 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.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.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-CDA can have deleterious effects in vivo.

  9. A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease

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    Van Leuven Fred

    2005-10-01

    Full Text Available Abstract Background Alzheimer's disease (AD is a progressive neurodegenerative disorder that primarily strikes the elderly. Studies in both humans and animal models have linked the consumption of cholesterol and saturated fats with amyloid-β (Aβ deposition and development of AD. Yet, these studies did not examine high fat diets in combination with reduced carbohydrate intake. Here we tested the effect of a high saturated fat/low carbohydrate diet on a transgenic mouse model of AD. Results Starting at three months of age, two groups of female transgenic mice carrying the "London" APP mutation (APP/V717I were fed either, a standard diet (SD composed of high carbohydrate/low fat chow, or a ketogenic diet (KD composed of very low carbohydrate/high saturated fat chow for 43 days. Animals fed the KD exhibited greatly elevated serum ketone body levels, as measured by β-hydroxybutyrate (3.85 ± 2.6 mM, compared to SD fed animals (0.29 ± 0.06 mM. In addition, animals fed the KD lost body weight (SD 22.2 ± 0.6 g vs. KD 17.5 ± 1.4 g, p = 0.0067. In contrast to earlier studies, the brief KD feeding regime significantly reduced total brain Aβ levels by approximately 25%. Despite changes in ketone levels, body weight, and Aβ levels, the KD diet did not alter behavioral measures. Conclusion Previous studies have suggested that diets rich in cholesterol and saturated fats increased the deposition of Aβ and the risk of developing AD. Here we demonstrate that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of Aβ. Therefore, dietary strategies aimed at reducing Aβ levels should take into account interactions of dietary components and the metabolic outcomes, in particular, levels of carbohydrates, total calories, and presence of ketone bodies should be considered.

  10. Complex of amyloid beta peptides with 24-hydroxycholesterol and its effect on hemicholinium-3 sensitive carriers

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Kopecký, V. Jr.; Hofbauerová, Kateřina; Hovorková, P.; Řípová, D.

    2008-01-01

    Roč. 33, č. 3 (2008), s. 412-421 ISSN 0364-3190 Grant - others:GA Mšk(CZ) MZOPCP2005 Institutional research plan: CEZ:AV0Z50200510 Keywords : aging * hippocampus * choline carriers Subject RIV: EE - Microbiology, Virology Impact factor: 2.260, year: 2008

  11. Uncoupling of M1 muscarinic receptor/G-protein interaction by amyloid beta(1-42)

    Czech Academy of Sciences Publication Activity Database

    Janíčková, Helena; Rudajev, Vladimír; Zimčík, Pavel; Jakubík, Jan; Tanila, H.; El-Fakahany, E. E.; Doležal, Vladimír

    2013-01-01

    Roč. 67, April (2013), s. 272-283 ISSN 0028-3908 R&D Projects: GA ČR(CZ) GA305/09/0681; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) 7E10060 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : Alzheimer ´s Disease * muscarinic receptors * G-proteins Subject RIV: ED - Physiology Impact factor: 4.819, year: 2013

  12. Development and Validation of Stability-Indicating GC-FID Method for the Quantitation of Memantine Hydrochloride and Its Nonchromophoric Impurities in Bulk and Pharmaceutical Dosages

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    Sanjay A. Jadhav

    2012-01-01

    Full Text Available A stability-indicating method has been developed and validated for the quantitative determination of memantine hydrochloride and its nonchromophoric impurities in drug substance and drug product using gas chromatography coupled with flame ionization detector (GC-FID. The stability-indicating nature of the method has been proved by establishing peak purity and confirming the mass balance of all samples by subjecting them to stress conditions like hydrolysis, oxidation, photolysis, and thermal degradation studies. The chromatographic separation was performed on a fused silica capillary (HP-5, 30 meter, 0.32 mm and 0.25 μm film thickness column. The method validation results indicate that the method has acceptable specificity, accuracy, linearity, precision, robustness, and high sensitivity with detection limits and quantitation limits ranging from 0.001% to 0.01% and 0.004% to 0.03%, respectively. The effectiveness of the technique was demonstrated by analysis of different bulk sample of Memantine hydrochloride. The proposed GC-FID method was also found to be specific and selective for the analysis of commercial formulation samples.

  13. Effects of memantine on cognition in patients with moderate to severe Alzheimer's disease: post-hoc analyses of ADAS-cog and SIB total and single-item scores from six randomized, double-blind, placebo-controlled studies.

    Science.gov (United States)

    Mecocci, Patrizia; Bladström, Anna; Stender, Karina

    2009-05-01

    The post-hoc analyses reported here evaluate the specific effects of memantine treatment on ADAS-cog single-items or SIB subscales for patients with moderate to severe AD. Data from six multicentre, randomised, placebo-controlled, parallel-group, double-blind, 6-month studies were used as the basis for these post-hoc analyses. All patients with a Mini-Mental State Examination (MMSE) score of less than 20 were included. Analyses of patients with moderate AD (MMSE: 10-19), evaluated with the Alzheimer's disease Assessment Scale (ADAS-cog) and analyses of patients with moderate to severe AD (MMSE: 3-14), evaluated using the Severe Impairment Battery (SIB), were performed separately. The mean change from baseline showed a significant benefit of memantine treatment on both the ADAS-cog (p ADAS-cog single-item analyses showed significant benefits of memantine treatment, compared to placebo, for mean change from baseline for commands (p < 0.001), ideational praxis (p < 0.05), orientation (p < 0.01), comprehension (p < 0.05), and remembering test instructions (p < 0.05) for observed cases (OC). The SIB subscale analyses showed significant benefits of memantine, compared to placebo, for mean change from baseline for language (p < 0.05), memory (p < 0.05), orientation (p < 0.01), praxis (p < 0.001), and visuospatial ability (p < 0.01) for OC. Memantine shows significant benefits on overall cognitive abilities as well as on specific key cognitive domains for patients with moderate to severe AD. (c) 2009 John Wiley & Sons, Ltd.

  14. Effect of donepezil in patients with Alzheimer's disease previously untreated or treated with memantine or nootropic agents in Germany: an observational study.

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    Klinger, Tatjana; Ibach, Bernd; Schoenknecht, Peter; Kamleiter, Martin; Silver, Gabrielle; Schroeder, Johannes; Mielke, Ruediger

    2005-05-01

    This open-label, prospective, observational, Post-Marketing Surveillance (PMS) study assessed the efficacy and safety of donepezil in patients who had been switched from therapies currently used in Germany to treat Alzheimer's disease (AD), such as memantine and nootropics, due to insufficient efficacy or poor tolerability. A treatment-naive population was included as a comparator. Patients with AD were treated with donepezil and observed for a period of approximately 3 months. A cognitive assessment was made using the Mini-Mental State Examination (MMSE). Quality of life (QoL) was assessed by the investigators who answered the question 'How did therapy with donepezil influence the QoL of the patient and/or his family over the observation period?' and was graded using three ratings: improved/unchanged/worsened. Adverse events (AEs) were also monitored. A total of 913 patients entered the study (mean +/- SD MMSE score 18.03 +/- 5.34). Efficacy assessments were analyzed for three groups: an overall group of patients who had received any form of prior AD drug therapy (N+ group; n = 709); a subgroup of patients from the N+ group who had received prior memantine therapy only (M+ group; n = 111) and patients who were drug treatment naive (N- group; n = 204). In the evaluable population donepezil improved MMSE scores by 2.21 +/- 3.47 points on average, with similar improvements observed in all three groups. QoL was judged to be improved in at least 70% of patients, again with similar results obtained for all three groups. Donepezil was well tolerated, with 85 of 913 (9.3%) patients reporting AEs. The most common AEs were those typically seen with cholinergic therapies (i.e., diarrhoea, vomiting and nausea). In this observational PMS study, donepezil was shown to be efficacious and well tolerated in patients who were being insufficiently treated with memantine or nootropic therapy. The magnitude of response was similar to that observed in patients who were previously

  15. Disease-modifying drugs in Alzheimer's disease

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    Ghezzi L

    2013-12-01

    Full Text Available Laura Ghezzi, Elio Scarpini, Daniela Galimberti Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy Abstract: Alzheimer's disease (AD is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, memantine, disease-modifying drugs, diagnosis, treatment

  16. Amiloride but not memantine reduces neurodegeneration, seizures and myoclonic jerks in rats with cardiac arrest-induced global cerebral hypoxia and reperfusion.

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    Tai, Kwok Keung; Truong, Daniel D

    2013-01-01

    It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.

  17. Amiloride but not memantine reduces neurodegeneration, seizures and myoclonic jerks in rats with cardiac arrest-induced global cerebral hypoxia and reperfusion.

    Directory of Open Access Journals (Sweden)

    Kwok Keung Tai

    Full Text Available It has been reported that both activation of N-methyl-D-aspartate receptors and acid-sensing ion channels during cerebral ischemic insult contributed to brain injury. But which of these two molecular targets plays a more pivotal role in hypoxia-induced brain injury during ischemia is not known. In this study, the neuroprotective effects of an acid-sensing cation channel blocker and an N-methyl-D-aspartate receptor blocker were evaluated in a rat model of cardiac arrest-induced cerebral hypoxia. We found that intracisternal injection of amiloride, an acid-sensing ion channel blocker, dose-dependently reduced cerebral hypoxia-induced neurodegeneration, seizures, and audiogenic myoclonic jerks. In contrast, intracisternal injection of memantine, a selective uncompetitive N-methyl-D-aspartate receptor blocker, had no significant effect on cerebral hypoxia-induced neurodegeneration, seizure and audiogenic myoclonic jerks. Intracisternal injection of zoniporide, a specific sodium-hydrogen exchanger inhibitor, before cardiac arrest-induced cerebral hypoxia, also did not reduce cerebral hypoxia-induced neurodegeneration, seizures and myoclonic jerks. These results suggest that acid-sensing ion channels play a more pivotal role than N-methyl-D-aspartate receptors in mediating cerebral hypoxia-induced brain injury during ischemic insult.

  18. Eficácia da memantina na doença de Alzheimer em seus estágios moderado a grave Efficacy of memantine in moderate to severe Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Rosana Soares Araújo

    2006-01-01

    Full Text Available INTRODUÇÃO: O objetivo desta revisão de literatura é avaliar a eficácia, a segurança e a tolerabilidade da memantina, um antagonista não-competitivo do receptor N-metil-D-aspartato (NMDA, no tratamento da doença de Alzheimer em seus estágios moderado a grave. MÉTODOS: Realizou-se uma busca no banco de dados MEDLINE com as palavras-chave memantine e Alzheimer's disease, sendo inseridos apenas ensaios clínicos randomizados, duplo-cegos e controlados com placebo. RESULTADOS: Foram incluídos quatro estudos que preenchiam os critérios de inclusão supracitados, realizados com pacientes portadores de doença de Alzheimer com grau moderado a grave. Todos os estudos indicaram um efeito benéfico da memantina com relação ao placebo para os seguintes parâmetros: melhora da capacidade funcional e maior participação nas atividades diárias. Dois estudos evidenciaram melhora cognitiva. A duração média dos estudos foi de 28 semanas e as doses mais eficazes variaram de 10 a 20mg/dia. Os efeitos adversos, em todos os estudos, foram maiores no grupo placebo. DISCUSSÃO: Apesar de ser uma droga nova e ainda de custo elevado, a memantina parece reduzir os custos totais e o tempo gasto do cuidador, além de produzir melhora global do paciente, gerando melhor qualidade de vida tanto para o paciente quanto para o cuidador. Estudos ainda não publicados, contudo, sugerem que o impacto dessa droga nos estágios mais avançados da demência de Alzheimer seja marginal.INTRODUCTION: The aim of this systematic review is to evaluate efficacy, safety and tolerability of memantine, a non-competitive agonist of N-methyl-D-aspartate (NMDA receptor, on the treatment of moderate to severe Alzheimer disease. METHODS: A search in MEDLINE database was made using key words memantine and Alzheimer's disease. Only randomized, double-blinded and placebo controlled clinical trials were included. RESULTS: Four studies were found that fulfilled inclusion criteria; all

  19. Ameliorating effect of anti-Alzheimer’s drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer’s disease

    Science.gov (United States)

    Elgharabawy, Rehab M; AL-Najjar, Amal H

    2017-01-01

    Mild to severe forms of nervous system damage were exhibited by approximately 60–70% of diabetics. It is important to understand the association between type 2 diabetes mellitus and Alzheimer’s disease. The aim of the present work is to understand the bidirectional association between type 2 diabetes and Alzheimer’s disease pathogenesis, that was monitored by glycaemic status, lipid profile, amyloid beta 40 and 42 (Aβ40 and Aβ42), C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer and magnesium measurements, to assess the association between theses biochemical markers and each other, to estimate the possibility of utilizing the amyloid beta as biochemical marker of T2D in Alzheimer's patients, and to evaluate the effect of piracetam and memantine drugs on diabetes mellitus. This study involved 120 subjects divided into 20 healthy control (group I), 20 diabetic patients (group II), 20 Alzheimer’s patients (group III), 20 diabetic Alzheimer's patients with symptomatic treatment (group IV), 20 diabetic Alzheimer's patients treated with memantine (group V), and 20 diabetic Alzheimer's patients treated with piracetam (group VI). The demographic characteristics, diabetic index, and lipid profile were monitored. Plasma amyloid beta 40 and amyloid beta 42, C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer, and magnesium were assayed. The levels of amyloid beta 40 and amyloid beta 42 were significantly elevated in diabetic Alzheimer's patients with symptomatic treatment (group IV) compared to group II (by 50.5 and 7.5 fold, respectively) and group III (by 25.4 and 2.8 fold, respectively). In groups II, III, IV, V and VI, significant and positive associations were monitored between insulin and amyloid beta 40, amyloid beta 42, C-reactive protein, total creatine kinase, and D-dimer. Diabetic markers were significantly decreased in diabetic Alzheimer’s patients treated with anti-Alzheimer’s drugs

  20. Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure.

    Science.gov (United States)

    McKay, Sean; Bengtson, C Peter; Bading, Hilmar; Wyllie, David J A; Hardingham, Giles E

    2013-11-01

    MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to 'pre-block' a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg(2+) is also present. In the presence of Mg(2+), 50% recovery from MK-801 blockade is achieved after 10' of 100 μM NMDA, or 30' of 15 μM NMDA exposure. In Mg(2+)-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg(2+) in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg(2+) or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg(2+) for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 'pre-block' protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Expression of active secreted forms of human amyloid beta-protein precursor by recombinant baculovirus-infected insect cells.

    OpenAIRE

    Bhasin, R; Van Nostrand, W E; Saitoh, T; Donets, M A; Barnes, E A; Quitschke, W W; Goldgaber, D

    1991-01-01

    Three alternatively spliced forms of the amyloid precursor protein (APP), APP-695, APP-751, and APP-770, were expressed in the baculovirus expression vector system. The recombinant proteins were secreted into the culture medium by infected insect cells, and APP molecules were detected in insect cells and medium 2 days after infection with the recombinant APP-baculoviruses. A partial sequence of the NH2 terminus of the secreted protein revealed identity with the native secreted protein and sho...

  2. Allosteric modulation of PS1/gamma-secretase conformation correlates with amyloid beta(42/40 ratio.

    Directory of Open Access Journals (Sweden)

    Kengo Uemura

    Full Text Available BACKGROUND: Presenilin 1(PS1 is the catalytic subunit of gamma-secretase, the enzyme responsible for the Abeta C-terminal cleavage site, which results in the production of Abeta peptides of various lengths. Production of longer forms of the Abeta peptide occur in patients with autosomal dominant Alzheimer disease (AD due to mutations in presenilin. Many modulators of gamma-secretase function have been described. We hypothesize that these modulators act by a common mechanism by allosterically modifying the structure of presenilin. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis we generated a genetically encoded GFP-PS1-RFP (G-PS1-R FRET probe that allows monitoring of the conformation of the PS1 molecule in its native environment in live cells. We show that G-PS1-R can be incorporated into the gamma-secretase complex, reconstituting its activity in PS1/2 deficient cells. Using Förster resonance energy transfer (FRET-based approaches we show that various pharmacological and genetic manipulations that target either gamma-secretase components (PS1, Pen2, Aph1 or gamma-secretase substrate (amyloid precursor protein, APP and are known to change Abeta(42 production are associated with a consistent conformational change in PS1. CONCLUSIONS/SIGNIFICANCE: These results strongly support the hypothesis that allosteric changes in PS1 conformation underlie changes in the Abeta(42/40 ratio. Direct measurement of physiological and pathological changes in the conformation of PS1/gamma-secretase may provide insight into molecular mechanism of Abeta(42 generation, which could be exploited therapeutically.

  3. Effect of creatine supplementation on cognitive performance and apoptosis in a rat model of amyloid-beta-induced Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Malek Alimohammadi-Kamalabadi

    2016-11-01

    Conclusion: Cr supplementation before and after β-amyloid injection into the CA1 area of hippocampus deteriorates the learning and memory impairment of rats and it does not protect neuronal apoptosis caused by β-amyloid.

  4. Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer's disease rats.

    Science.gov (United States)

    Lee, Jae-Min; Shin, Mal-Soon; Ji, Eun-Sang; Kim, Tae-Woon; Cho, Han-Sam; Kim, Chang-Ju; Jang, Myung-Soo; Kim, Tae-Wook; Kim, Bo-Kyun; Kim, Dong-Hee

    2014-10-01

    Alzheimer's disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25-35-induced AD rats. AD was induced by a bilateral intracerebroventricular (ICV) injection of Aβ25-35. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, starting 2 days after Aβ25-35 injection. In the present results, ICV injection of Aβ25-35 deteriorated motor coordination and balance. The number of calbindin-positive cells in the cerebellar vermis was decreased and glial fibrillary acidic protein (GFAP) expression in the cerebellar vermis was increased in the Aβ25-35-induced AD rats. Treadmill exercise improved motor coordination and balance. Treadmill exercise increased the number of Purkinje neurons and suppressed GFAP expression in the cerebellar vermis. The present study demonstrated that treadmill exercises alleviated dysfunction of motor coordination and balance by reduction of Purkinje cell loss through suppressing reactive astrocytes in the cerebellum of AD rats. The present study provides the possibility that treadmill exercise might be an important therapeutic strategy for the symptom improvement of AD patients.

  5. Additional Value of CSF Amyloid-beta(40) Levels in the Differentiation between FTLD and Control Subjects

    NARCIS (Netherlands)

    Verwey, N.A.; Kester, M.I.; van der Flier, W.M.; Veerhuis, R.; Berkhof, J.; Twaalfhoven, H.A.M.; Blankenstein, M.A.; Scheltens, P.; Pijnenburg, Y.A.L.

    2010-01-01

    To determine the additional value of cerebrospinal fluid (CSF) amyloid-β {1-40} (Aβ {40}) next to amyloid-β {1-42} (β {42}), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls,

  6. Protective role of rosmarinic acid on amyloid beta 42-induced echoic memory decline: Implication of oxidative stress and cholinergic impairment.

    Science.gov (United States)

    Kantar Gok, Deniz; Hidisoglu, Enis; Ocak, Guzide Ayse; Er, Hakan; Acun, Alev Duygu; Yargıcoglu, Piraye

    2018-04-13

    In the present study, we examined whether rosmarinic acid (RA) reverses amyloid β (Aβ) induced reductions in antioxidant defense, lipid peroxidation, cholinergic damage as well as the central auditory deficits. For this purpose, Wistar rats were randomly divided into four groups; Sham(S), Sham + RA (SR), Aβ42 peptide (Aβ) and Aβ42 peptide + RA (AβR) groups. Rat model of Alzheimer was established by bilateral injection of Aβ42 peptide (2,2 nmol/10 μl) into the lateral ventricles. RA (50 mg/kg, daily) was administered orally by gavage for 14 days after intracerebroventricular injection. At the end of the experimental period, we recorded the auditory event related potentials (AERPs) and mismatch negativity (MMN) response to assess auditory functions followed by histological and biochemical analysis. Aβ42 injection led to a significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and 4-Hydroxy-2-nonenal (4-HNE) but decreased the activity of antioxidant enzymes (SOD, CAT, GSH-Px) and glutathione levels. Moreover, Aβ42 injection resulted in a reduction in the acetylcholine content and acetylcholine esterase activity. RA treatment prevented the observed alterations in the AβR group. Furthermore, RA attenuated the increased Aβ staining and astrocyte activation. We also found that Aβ42 injection decreased the MMN response and theta power/coherence of AERPs, suggesting an impairing effect on auditory discrimination and echoic memory processes. RA treatment reversed the Aβ42 related alterations in AERP parameters. In conclusion, our study demonstrates that RA prevented Aβ-induced antioxidant-oxidant imbalance and cholinergic damage, which may contribute to the improvement of neural network dynamics of auditory processes in this rat model. Copyright © 2018. Published by Elsevier Ltd.

  7. Simple detection method of amyloid-beta peptide using p-FET with optical filtering layer and magnetic particle

    Science.gov (United States)

    Kim, Kwan-Soo; Kim, Chang-Beom; Song, Ki-Bong

    2013-05-01

    This article describes a novel method for detection of amyloid-β (Aβ) peptide that utilizes a photo-sensitive field-effect transistor (p-FET). According to a recent study, Aβ protein is known to play a central role in the pathogenesis of Alzheimer's disease (AD). Accordingly, we investigated the variation of photo current of the p-FET generated by the magnetic beads conjugated with Aβ peptides which are placed on the p-FET sensing areas. Additionally, in order to amplify the output signal, we used the lock-in amplifier (LIA) and confirmed the generating the photo current by a small incident light power under 100 μW. It means that it is possible to simply detect a certain protein using magnetic beads conjugated with Aβ peptide and fluorescent label located on the p-FET device. Therefore, in this paper, we suggest that our method could detect tiny amounts of Aβ peptide for early diagnosis of AD using the p-FET devices.

  8. Acetylcholineestarase-Inhibiting Alkaloids from Lycoris radiata Delay Paralysis of Amyloid Beta-Expressing Transgenic C. elegans CL4176

    OpenAIRE

    Xin, Lijuan; Yamujala, Ritupriya; Wang, Yuehu; Wang, Huan; Wu, Wen-Hsuan; Lawton, Michael A.; Long, Chunlin; Di, Rong

    2013-01-01

    The limited symptom relief and side effects of current Alzheimer's disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid β-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aβ1-42 is induced, to study two natural benzylphenethyl...

  9. Acetylcholineestarase-inhibiting alkaloids from Lycoris radiata delay paralysis of amyloid beta-expressing transgenic C. elegans CL4176.

    Directory of Open Access Journals (Sweden)

    Lijuan Xin

    Full Text Available The limited symptom relief and side effects of current Alzheimer's disease (AD medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid β-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aβ1-42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L' Her. Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Aβ-toxicity in C. elegans.

  10. Acetylcholineestarase-inhibiting alkaloids from Lycoris radiata delay paralysis of amyloid beta-expressing transgenic C. elegans CL4176.

    Science.gov (United States)

    Xin, Lijuan; Yamujala, Ritupriya; Wang, Yuehu; Wang, Huan; Wu, Wen-Hsuan; Lawton, Michael A; Long, Chunlin; Di, Rong

    2013-01-01

    The limited symptom relief and side effects of current Alzheimer's disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid β-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aβ1-42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L' Her.) Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Aβ-toxicity in C. elegans.

  11. Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease rats.

    Science.gov (United States)

    Kim, Bo-Kyun; Shin, Mal-Soon; Kim, Chang-Ju; Baek, Sang-Bin; Ko, Yeong-Chan; Kim, Young-Pyo

    2014-02-01

    Alzheimer's disease is one of the most devastating neurodegenerative disorders, and this disease is characterized by severe memory impairment and decline of cognition. Hippocampal neurons are vulnerable to injury induced by Alzheimer's disease. Physical exercise is known to promote cell survival and functional recovery after brain injuries. In the present study, we investigated the effects of treadmill exercise on short-term memory in relation with neurogenesis in the rats with amyloid β25-35 (Aβ25-35)-induced Alzheimer's disease. The rat model of Alzheimer's disease was induced by the intracerebroventricular (ICV) injection of Aβ25-35, using a stereotaxic instrument. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 4 consecutive weeks, starting 2 days after Aβ25-35 injection. Presently, short-term memory was deteriorated and apical dendritic length in the hippocampus was shortened in the hippocampus by Aβ25-35 injection. In contrast, treadmill exercise alleviated memory impairment and increased apical dendritic length in the Aβ25-35-injected rats. Neurogenesis and brain-derived neurotorphic factor (BDNF) and tyrosine kinase B (trkB) in the hippocampal dentate gyrus were decreased by Aβ25-35 injection. Treadmill exercise increased neurogenesis and expressions of BDNF and trkB expressions. The present study shows that treadmill exercise may provide therapeutic value for the alleviating symptoms of Alzheimer's disease.

  12. Vascular remodeling versus amyloid beta-induced oxidative stress in the cerebrovascular dysfunctions associated with Alzheimer's disease.

    Science.gov (United States)

    Tong, Xin-Kang; Nicolakakis, Nektaria; Kocharyan, Ara; Hamel, Edith

    2005-11-30

    The roles of oxidative stress and structural alterations in the cerebrovascular dysfunctions associated with Alzheimer's disease (AD) were investigated in transgenic mice overexpressing amyloid precusor protein (APP+) or transforming growth factor-beta1 (TGF+). Age-related impairments and their in vitro reversibility were evaluated, and underlying pathogenic mechanisms were assessed and compared with those seen in AD brains. Vasoconstrictions to 5-HT and endothelin-1 were preserved, except in the oldest (18-21 months of age) TGF+ mice. Despite unaltered relaxations to sodium nitroprusside, acetylcholine (ACh) and calcitonin gene-related peptide-mediated dilatations were impaired, and there was an age-related deficit in the basal availability of nitric oxide (NO) that progressed more gradually in TGF+ mice. The expression and progression of these deficits were unrelated to the onset or extent of thioflavin-S-positive vessels. Manganese superoxide dismutase (SOD2) was upregulated in pial vessels and around brain microvessels of APP+ mice, pointing to a role of superoxide in the dysfunctions elicited by amyloidosis. In contrast, vascular wall remodeling associated with decreased levels of endothelial NO synthase and cyclooxygenase-2 and increased contents of vascular endothelial growth factor and collagen-I and -IV characterized TGF+ mice. Exogenous SOD or catalase normalized ACh dilatations and NO availability in vessels from aged APP+ mice but had no effect in those of TGF+ mice. Increased perivascular oxidative stress was not evidenced in AD brains, but vascular wall alterations compared well with those seen in TGF+ mice. We conclude that brain vessel remodeling and associated alterations in levels of vasoactive signaling molecules are key contributors to AD cerebrovascular dysfunctions.

  13. Analysis of the complex between amyloid beta peptides and mitochondrial enzyme 17beta-HSD in cerebrospinal fluid

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Hegnerová, Kateřina; Bocková, Markéta; Vaisocherová, Hana; Bartoš, A.; Říčný, J.; Řípová, D.; Homola, J.

    2008-01-01

    Roč. 275, podzim (2008), s. 249-249 ISSN 1742-464X. [EUROPTRODE /9./. Dublin, 30.03.2008-02.04.2008] Institutional research plan: CEZ:AV0Z20670512 Keywords : surface plasmon resonance * alzheimer disease * 17beta-HSD10 Subject RIV: JB - Sensors, Measurment, Regulation Impact factor: 3.139, year: 2008

  14. Intracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Thomas A Bayer

    2010-03-01

    Full Text Available Despite of long-standing evidence that beta-amyloid (Aβ peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

  15. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae

    DEFF Research Database (Denmark)

    Hansson Petersen, Camilla A; Alikhani, Nyosha; Behbahani, Homira

    2008-01-01

    by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show...... to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane...... potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown...

  16. Lower GI Series

    Science.gov (United States)

    ... single-contrast lower GI series, which uses only barium during the test • a double-contrast or air-contrast lower GI series, which uses ... to evenly coat the large intestine with the barium • if the health care provider has ordered a double-contrast lower GI series, the radiologist will inject air ...

  17. A matrix lower bound

    Energy Technology Data Exchange (ETDEWEB)

    Grcar, Joseph F.

    2002-02-04

    A matrix lower bound is defined that generalizes ideas apparently due to S. Banach and J. von Neumann. The matrix lower bound has a natural interpretation in functional analysis, and it satisfies many of the properties that von Neumann stated for it in a restricted case. Applications for the matrix lower bound are demonstrated in several areas. In linear algebra, the matrix lower bound of a full rank matrix equals the distance to the set of rank-deficient matrices. In numerical analysis, the ratio of the matrix norm to the matrix lower bound is a condition number for all consistent systems of linear equations. In optimization theory, the matrix lower bound suggests an identity for a class of min-max problems. In real analysis, a recursive construction that depends on the matrix lower bound shows that the level sets of continuously differential functions lie asymptotically near those of their tangents.

  18. Lower Barthel Index scores predict less prescription of pharmacological therapy in elderly patients with Alzheimer disease.

    Science.gov (United States)

    Formiga, Francesc; Fort, Isabel; Robles, Maria Jose; Rodriguez, Daniel; Regalado, Pedro

    2010-01-01

    To determine the factors associated with receiving specific treatment (cholinesterase inhibitors or/and memantine) for Alzheimer disease (AD) in elderly patients. An observational study carried out in 289 consecutive outpatients aged >64 years with dementia. We collected data on specific AD therapy, sociodemographic variables, Barthel Index (BI), Lawton and Brody Index (LI), Mini Mental State Examination, Global Deterioration Scale (GDS), Charlson Index and the total number of drugs chronically prescribed. Patients receiving specific therapy for dementia were compared with the rest. Two hundred and thirty-three (80.6%) patients were receiving specific treatment for dementia, with 197 (84.5%) receiving monotherapy and the rest (15.4%) combined therapy. The bivariate analysis showed that age, marital status, place of residence, BI and LI, cognitive status and disease severity (GDS) were factors associated with receiving specific dementia therapy. Multiple stepwise logistic regression analysis showed that a lower BI (beta = -0.25; odds ratio 0.976, 95% confidence interval = 0.966-0.986; p < 0.0001) was the only factor independently associated with not receiving specific therapy for AD. Of the possible factors related to elderly patients receiving specific therapy for AD, a poor BI score was the most important factor associated with not receiving treatment. 2010 S. Karger AG, Basel.

  19. Lower thoracic syndrome.

    Science.gov (United States)

    Farooq, Muhammad Nazim

    2017-01-01

    The role of thoracic spine related dysfunction in producing lower extremity symptoms is not clear. This case study describes the assessment and treatment of a patient with low back pain and bilateral lower extremity (BLE) symptoms. It was found that patient education about postural awareness and passive mobilization are valuable aids to decrease BLE symptoms due to sympathetic nervous system (SNS) dysfunction and lower thoracic hypomobility. The clinicians need to consider examination and treatment of the lower thoracic area in patients with BLE symptoms. More research is required to explore the role of SNS dysfunction in producing BLE symptoms.

  20. Lower pole stones

    DEFF Research Database (Denmark)

    Sanguedolce, Francesco; Breda, Alberto; Millan, Felix

    2013-01-01

    PURPOSE: To assess efficacy and safety of prone- and supine percutaneous nephrolithotomy (PCNL) for the treatment of lower pole kidney stones. METHODS: Data from patients affected by lower pole kidney stones and treated with PCNL between December 2005 and August 2010 were collected retrospectively...... by seven referral centres. Variables analysed included patient demographics, clinical and surgical characteristics, stone-free rates (SFR) and complications. Statistical analysis was conducted to compare the differences for SFRs and complication rates between prone- and supine PCNL. RESULTS: One hundred...... seventeen patients underwent PCNL (mean stone size: 19.5 mm) for stones harboured only in the lower renal pole (single stone: 53.6 %; multiple stones: 46.4 %). A higher proportion of patients with ASA score ≥ 3 and harbouring multiple lower pole stones were treated with supine PCNL (5.8 vs. 23.1 %; p = 0...

  1. Lower Extremity Paralysis.

    Science.gov (United States)

    Glancy, D Luke; Subramaniam, Pramilla N; Rodriguez, Juan F

    2016-11-15

    Severe hypokalemia in the absence of other electrolyte abnormalities, the result of diarrhea, caused striking electrocardiographic changes, generalized weakness, flaccid paralysis of the lower extremities, and biochemical evidence of mild skeletal and cardiac rhabdomyolysis in a 33-year-old man. Repletion of potassium reversed all abnormalities in 24 hours. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Acute lower extremity ischaemia

    African Journals Online (AJOL)

    often defined as a sudden loss of perfusion to the lower extremity/extremities of less than 14 days' duration, ... Femoral arteries palpated Soft, tender. Hard, calcified. Dystrophic limb features Absent. Present. Cardiac abnormalities Present. Generally absent. Iliac/femoral bruits Absent. May be present. History of claudication ...

  3. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

    Directory of Open Access Journals (Sweden)

    Yong-lin Zhao

    2016-01-01

    Full Text Available Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser 404 (p-tau (S 404 , and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S 404 levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury.

  4. Lower gastrointestinal endoscopies results

    Directory of Open Access Journals (Sweden)

    Ahmet Bozdağ

    2014-12-01

    Full Text Available Objectives: Endoscopic examinations have great potential in early diagnosis of colorectal adenomas and carcinomas with reducing to colorectal cancer incidence and mortality. We aimed to evaluate for diagnostic purposeful lower gastrointestinal endoscopic procedures in the second step state hospital retrospectively Methods: Between June 2010 and June 2013, we evaluated 278 patients with rectal bleeding, constipation and abdominal pain detected by lower gastrointestinal endoscopic procedures retrospectively. Results: The mean age of the patients was 54.8 ± 16.8 (15-90 year, respectively. 172 (61.9% of the patients were male and 106 (38.1% of the patients were female. 116 (41.7% of the patients was performed rectosigmoidoscopy and 162 (58.3% of the patients was performed colonoscopy. 51(18.3% of our patients were normal. 10 (3.6% of patients had colorectal cancer, 11(3.9% of patients had inflammatory bowel disease, 8 (2.9% of patients had parasitosis, 31(11.1% of patients had colorectal polyps, 12 (4.3% , in patients had diverticular disease, 2 (0.7% patients had rectal ulcer, 25 (9% patients had anal fissure and 159 (57.2% of the patients had hemorrhoidal disease. Conclusion: Lower gastrointestinal endoscopy is a method been the gold standard with a low complication rate and that can be easily applied in the evaluation to pathology of colorectal and anal canal. J Clin Exp Invest 2014; 5 (4: 580-582

  5. Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

    Science.gov (United States)

    Peng, Liang; Wu, Chun-Hua; Cao, Hong; Zhong, John F.; Hoffman, Jill; Huang, Sheng-He

    2015-01-01

    Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer’s disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial

  6. Advanced Structure-activity Relationships Applied to Mentha spicata L. Subsp. spicata Essential Oil Compounds as AChE and NMDA Ligands, in Comparison with Donepezil, Galantamine and Memantine - New Approach in Brain Disorders Pharmacology.

    Science.gov (United States)

    Avram, Speranta; Mernea, Maria; Bagci, Eyup; Hritcu, Lucian; Borcan, Livia-Cristina; Mihailescu, Dan Florin

    2017-01-01

    Alzheimer's disease (AD) therapy is based on several natural and synthetic compounds that act as acetylcholinesterase (AChE) and N-methyl-D-aspartate receptor (NMDA) ligands that have limited efficiency in relieving AD symptoms. Recent studies show that inhibitors isolated from Mentha spicata L. subsp. spicata are promising for AD therapy. We aimed to identify novel and more potent phytopharmaceutical compounds for AD treatment by taking into account the compounds from Mentha spicata L. subsp. spicata essential oil. We generated structure-activity relationship (SAR) models that predict the biological activities of 14 Mentha spicata L. subsp. spicata compounds on AChE and NMDA by comparing their molecular features with those of the three conventional ligands: donepezil, galantamine and memantine. The most relevant descriptors for predicting the biological activities of considered compounds are solvent accessible area and their subdivided, hydrophobicity, energy of frontier molecular orbitals and counts of the aromatic ring and rotatable bounds. 1,8-cineole, the main compound from Mentha spicata L. subsp. spicata essential oil, resulted to be similar with memantine and dissimilar with donepezil in respect to hidrophobicity (logP1,8-cineole=2.95, logPmemantine=2.81, logPdonepezil=4.11), the energy of LUMO (eLUMO1,8-cineole=3.01 eV, eLUMOmemantine=3.35 eV, eLUMOdonepezil=-0.35 eV) and the solvent accessible surface areas over all hydrophobic (SA_H1,8-cineole= 350 Å2, SA_Hmemantine= 358 Å2, SA_Hdonepezil= 655 Å2) or polar atoms (SA_P1,8-cineole= 4 Å2, SA_Pmemantine=10 Å2, SA_Pdonepezil=44.62 Å2). Our results point towards 1,8-cineole as a good candidate for NMDA antagonism, with a weaker AChE inhibitory effect. Our results may be useful in establishing new therapeutic strategies for neurological disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli-Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses.

    Directory of Open Access Journals (Sweden)

    Jing-Yi Yu

    Full Text Available Neonatal sepsis and meningitis (NSM remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR, an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM, a FDA-approved drug for treatment of Alzheimer's disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44 and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to

  8. Crane Lowers Aeroshell

    Science.gov (United States)

    2003-01-01

    January 31, 2003In the Payload Hazardous Servicing Facility, an overhead crane lowers the Mars Exploration Rover (MER) aeroshell toward a rotation stand. Set to launch in 2003, the MER Mission will consist of two identical rovers designed to cover roughly 110 yards (100 meters) each Martian day. Each rover will carry five scientific instruments that will allow it to search for evidence of liquid water that may have been present in the planet's past. The rovers will be identical to each other, but will land at different regions of Mars. The first rover has a launch window opening May 30, and the second rover a window opening June 25, 2003.

  9. Vitiligo Lateral Lower Lip

    Directory of Open Access Journals (Sweden)

    Sahoo Antaryami

    2002-01-01

    Full Text Available Vitiligo characteristically affecting the lateral lower lip (LLL is a common presentation in South Orissa. This type of lesion has rarely been described in literature. One hundred eighteen such cases were studied during the period from October 1999 to September, 2000. LLL vitiligo constituted 16.39% of all vitiligo patients. Both sexes were affected equally. The peak age of onset was in the 2nd decade, mean duration of illness 21.46 months. Fifty six patients had unilateral lesion (38 on the left and 18 on the right. Among the 62 patients having bilateral lesions, the onset was more frequent on the left (38 than either the right (8 or both sides together (16. All the patients were right handed. Association with local factors like infection, trauma, cheilitis, FDE etc were associated in 38.98% of cases, but systemic or autoimmune diseases were not associated. Positive family history was found in 22% of cases.

  10. Reactor core lower support

    International Nuclear Information System (INIS)

    1981-01-01

    This patent refers to the lower support of a nuclear reactor core, and is intended for supporting each fuel assembly of the core and for distributing the primary coolant through these assemblies. It is composed of: - A first thick plate supporting the fuel assemblies. Vertical channels are machined in this plate directly facing each assembly for the passage of the primary fluid: - A second thin plate drilled with orifices, fixed under the first plate, with no space between them, and so positioned that each orifice is directly facing one of the channels. The section of the orifices diminishes from the centre of the plate towards its periphery. The second plate can also be constituted of an assembly of juxtaposed smaller plates, each small plate being secured to the first plate independently of the neighbouring plates [fr

  11. Tevatron lower temperature operation

    International Nuclear Information System (INIS)

    Theilacker, J.C.

    1994-07-01

    This year saw the completion of three accelerator improvement projects (AIP) and two capital equipment projects pertaining to the Tevatron cryogenic system. The projects result in the ability to operate the Tevatron at lower temperature, and thus higher energy. Each project improves a subsystem by expanding capabilities (refrigerator controls), ensuring reliability (valve box, subatmospheric hardware, and compressor D), or enhancing performance (cold compressors and coldbox II). In January of 1994, the Tevatron operated at an energy of 975 GeV for the first time. This was the culmination, of many years of R ampersand D, power testing in a sector (one sixth) of the Tevatron, and final system installation during the summer of 1993. Although this is a modest increase in energy, the discovery potential for the Top quark is considerably improved

  12. Lower gastrointestinal malignancies

    International Nuclear Information System (INIS)

    Minsky, Bruce D.

    1995-01-01

    Objective: This refresher course will review the current knowledge as well as ongoing and future research strategies in lower gastrointestinal malignancies. Radiation therapy has a significant role in the adjuvant treatment of lower gastrointestinal malignancies. Furthermore, there are data to suggest that radiation therapy is an integral component of the conservative management (organ preservation) of rectal and anal cancers. 1. Colon cancer. The standard adjuvant treatment for node positive or high risk transmural colon cancer is postoperative 5-FU and Levamisole. There are retrospective data to suggest that certain subsets of high risk patients may benefit from postoperative radiation therapy. 2. Rectal cancer. Randomized trials have revealed an advantage of postoperative radiation therapy plus chemotherapy in transmural and/or node positive rectal cancer. In the adjuvant setting the use of continuous infusion 5-FU may be more beneficial compared with bolus 5-FU. Despite the improvement in survival, postoperative therapies are associated with an approximately 35% incidence of grade 3+ toxicity. Recent data suggest that the use of preoperative combined modality therapy may be associated with less toxicity as well as increase the chance of sphincter preservation. New Intergroup trials addressing these issues will be presented. In patients with locally advanced unresectable rectal cancer, the addition of intraoperative radiation therapy may further improve local control. 3. Anal cancer. The use of combined 5-FU/Mitomycin-C and pelvic radiation therapy is effective in the treatment of anal carcinoma. The RTOG has recently completed a randomized trial addressing the question of the effectiveness and toxicity of Mitomycin-C. The replacement Intergroup Phase III trial will be presented

  13. Lower gastrointestinal malignancies

    International Nuclear Information System (INIS)

    Minsky, Bruce D.

    1996-01-01

    Objective: This refresher course will review the current knowledge as well as ongoing and future research strategies in lower gastrointestinal malignancies. Radiation therapy has a significant role in the adjuvant treatment of lower gastrointestinal malignancies. Furthermore, there are data to suggest that radiation therapy is an integral component of the conservative management (organ preservation) of rectal and anal cancers. 1. Colon cancer. The standard adjuvant treatment for node positive or high risk transmural colon cancer is postoperative 5-FU and Levamisole. There are retrospective data to suggest that certain subsets of high risk patients may benefit from postoperative radiation therapy. 2. Rectal cancer. Randomized trials have revealed an advantage of postoperative radiation therapy plus chemotherapy in transmural and/or node positive rectal cancer. In the adjuvant setting the use of continuous infusion 5-FU may be more beneficial compared with bolus 5-FU. Despite the improvement in survival, postoperative therapies are associated with an approximately 35% incidence of grade 3+ toxicity. Recent data suggest that the use of preoperative combined modality therapy may be associated with less toxicity as well as increase the chance of sphincter preservation. New Intergroup trials addressing these issues will be presented. In patients with locally advanced unresectable rectal cancer, the addition of intraoperative radiation therapy may further improve local control. 3. Anal cancer. The use of combined 5-FU/Mitomycin-C and pelvic radiation therapy is effective in the treatment of anal carcinoma. The RTOG has recently completed a randomized trial addressing the question of the effectiveness and toxicity of Mitomycin-C. The replacement Intergroup Phase III trial will be presented

  14. Exercises in Heavy Lowering

    CERN Multimedia

    2006-01-01

    Driving up to Point 5, one can't help but notice the impressively enormous red structure climbing up and over Building 3585. This unusual bridge-like construction is CMS'new crane, otherwise known as 'the gantry'. CMS'impressive "gantry" was recently installed at Building 3585. The 'gantry'was constructed by VSL, a Swiss company that is used to building such uniquely designed cranes used for major construction jobs, including lifting the roofs of various stadiums and the huge Airbus A380 assembly hall in Toulouse or bridge foundation caissons. CMS's crane was custom-built to sustain up to 2000 tonnes of machinery and detectors and slowly lower them down into the experimental cavern. The feature of two towers, one on either side of the building, each 24 m high, is the reason behind the nickname of this amazing crane. Two large beams, 28 m long and 3.4 m high, run along the width of the roof and four openings, each 5 m long, in the ceiling will allow the cables to pass through into the gallery. Unlike typic...

  15. Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus.

    Directory of Open Access Journals (Sweden)

    Anisur Rahman

    Full Text Available The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON and the N-methyl-D-aspartate antagonist memantine (MEM provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

  16. Effects of acute administration of donepezil or memantine on sleep-deprivation-induced spatial memory deficit in young and aged non-human primate grey mouse lemurs (Microcebus murinus).

    Science.gov (United States)

    Rahman, Anisur; Lamberty, Yves; Schenker, Esther; Cella, Massimo; Languille, Solène; Bordet, Régis; Richardson, Jill; Pifferi, Fabien; Aujard, Fabienne

    2017-01-01

    The development of novel therapeutics to prevent cognitive decline of Alzheimer's disease (AD) is facing paramount difficulties since the translational efficacy of rodent models did not resulted in better clinical results. Currently approved treatments, including the acetylcholinesterase inhibitor donepezil (DON) and the N-methyl-D-aspartate antagonist memantine (MEM) provide marginal therapeutic benefits to AD patients. There is an urgent need to develop a predictive animal model that is phylogenetically proximal to humans to achieve better translation. The non-human primate grey mouse lemur (Microcebus murinus) is increasingly used in aging research, but there is no published results related to the impact of known pharmacological treatments on age-related cognitive impairment observed in this primate. In the present study we investigated the effects of DON and MEM on sleep-deprivation (SD)-induced memory impairment in young and aged male mouse lemurs. In particular, spatial memory impairment was evaluated using a circular platform task after 8 h of total SD. Acute single doses of DON or MEM (0.1 and 1mg/kg) or vehicle were administered intraperitoneally 3 h before the cognitive task during the SD procedure. Results indicated that both doses of DON were able to prevent the SD-induced deficits in retrieval of spatial memory as compared to vehicle-treated animals, both in young and aged animals Likewise, MEM show a similar profile at 1 mg/kg but not at 0.1mg/kg. Taken together, these results indicate that two widely used drugs for mitigating cognitive deficits in AD were partially effective in sleep deprived mouse lemurs, which further support the translational potential of this animal model. Our findings demonstrate the utility of this primate model for further testing cognitive enhancing drugs in development for AD or other neuropsychiatric conditions.

  17. Lower GI Series (Barium Enema)

    Science.gov (United States)

    ... single-contrast lower GI series, which uses only barium a double-contrast or air-contrast lower GI series, which uses ... to evenly coat the large intestine with the barium. If you are having a double-contrast lower GI series, the radiologist will inject air ...

  18. Attitudes regarding lower extremity allotransplantation among lower extremity amputees.

    Science.gov (United States)

    Carty, Matthew J; Duclos, Antoine; Talbot, Simon G; Tullius, Stefan G; Pribaz, Julian J; Pomahac, Bohdan

    2014-12-01

    Lower limb allotransplantation is garnering increasing attention in the vascularized composite allotransplantation community as a potential treatment modality for those suffering from lower limb amputations. Little is known, however, about the level of interest among lower limb amputees regarding this procedure. An online survey regarding lower limb allotransplantation was designed in conjunction with and distributed by the Amputee Coalition to lower limb amputees in the United States. Responses from the survey were blinded, tabulated, and analyzed for significance using chi-square or Fisher's exact test. A total of 770 respondents completed the online survey. Forty-three percent of respondents stated they would be interested in being evaluated for lower limb transplantation, 36 percent declined, and 21 percent were uncertain. Those respondents who expressed an interest in allotransplantation tended to be significantly younger, better educated, more recently amputated, and less satisfied with prosthetic outcomes than those who were not interested. The most important criterion for transplantation to be considered a success by respondents was restoration of meaningful knee/ankle joint function, followed by restoration of limb sensibility. If immunosuppression were not required, 32 percent of those who initially declined and 88 percent of those who were uncertain would choose to undergo evaluation for lower limb allotransplantation. A significant proportion of lower limb amputees would be interested in undergoing evaluation for lower limb allotransplantation.

  19. The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42

    DEFF Research Database (Denmark)

    Søderman, Andreas; Thomsen, Morten Skøtt; Hansen, Henrik H

    2008-01-01

    systemic administration of the alpha7 nAChR agonist SSR180711 (10 mg/kg) result in a significant increase in Fos protein levels in the shell of nucleus accumbens in wild-type mice, but has no effect in the transgene mice. There were fewer cell bodies expressing Fos in the prefrontal cortex of transgene...... mice, and in this region no induction was achieved after administration with SSR180711 in either of the two groups. These results suggest that overexpression of human Abeta peptides perhaps via direct interaction with alpha7 nAChR, inhibit alpha7 nAChR-dependent neurotransmission in vivo and emphasize...

  20. Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort

    Directory of Open Access Journals (Sweden)

    Sang Won Seo

    2017-01-01

    Full Text Available Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ positron emission tomography (PET strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1, and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2. In experiment 1, 54 subjects with [11C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years were included. We assessed Thal amyloid phase (N = 36 and CERAD score (N = 54 versus both global and regional PiB SUVRs. In experiment 2 (N = 42, PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs, diffuse plaques (DPs and cerebral amyloid angiopathy (CAA to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR (p = 0.186 and 0.230. In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β = 0.414–0.804, p < 0.05, whereas DPs were independently correlated with PiB SUVR in the angular gyrus ROI (β = 0.446, p = 0.010. CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β = 0.222–0.355, p < 0.05. In conclusion, global PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.

  1. Resveratrol reduces amyloid-beta (Aβ₁₋₄₂)-induced paralysis through targeting proteostasis in an Alzheimer model of Caenorhabditis elegans.

    Science.gov (United States)

    Regitz, Charlotte; Fitzenberger, Elena; Mahn, Friederike Luise; Dußling, Lisa Marie; Wenzel, Uwe

    2016-03-01

    Resveratrol is a polyphenol present in red wine for which the capability of directly interfering with the hallmark of Alzheimer's disease (AD), i.e. toxic β-amyloid protein (Aβ) aggregation, has been shown recently. Since the stimulation of proteostasis could explain reduced Aβ-aggregation, we searched for proteostasis targets of resveratrol. The transgenic Caenorhabditis elegans strain CL2006, expressing Aβ1-42 under control of a muscle-specific promoter and responding to Aβ-toxicity with paralysis, was used as a model. Target identification was accomplished through specific knockdowns of proteostasis genes by RNA interference. Effects of resveratrol on protein aggregation were identified using ProteoStat(®) Detection Reagent, and activation of proteasomal degradation by resveratrol was finally proven using a specific fluorogenic peptide substrate. Resveratrol at a concentration of 100 µM caused a 40 % decrease in paralysis. UBL-5 involved in unfolded protein response (UPR) in mitochondria proved to be necessary for the prevention of Aβ-toxicity by resveratrol. Also XBP-1, which represents an endoplasmic reticulum-resident factor involved in UPR, was identified to be necessary for the effects of resveratrol. Regarding protein degradation pathways, the inhibition of macroautophagy and chaperone-mediated autophagy prevented resveratrol from reducing paralysis as did the inhibition of proteasomal degradation. Finally, resveratrol reduced the amount of lysosomes, suggesting increased flux of proteins through the autophagy pathways and activated proteasomal degradation. Resveratrol reduces the Aβ-induced toxicity in a C. elegans model of AD by targeting specific proteins involved in proteostasis and thereby reduces the amount of aggregated Aβ.

  2. Amyloid-beta (Aβ₁₋₄₂)-induced paralysis in Caenorhabditis elegans is inhibited by the polyphenol quercetin through activation of protein degradation pathways.

    Science.gov (United States)

    Regitz, Charlotte; Dußling, Lisa Marie; Wenzel, Uwe

    2014-10-01

    Dietary polyphenols are suggested to play a role in the prevention of Alzheimer's disease, of which accumulation of aggregated beta amyloid (Aβ) is a key histopathological hallmark. We used the transgenic Caenorhabditis elegans strain CL2006, which expresses human Aβ₁₋₄₂ under control of a muscle-specific promoter and responds to Aβ₁₋₄₂ aggregation with paralysis, to test effects of the polyphenol quercetin on the phenotype. Quercetin dose-dependently decreased the amount of aggregated proteins in solution and also paralysis in CL2006. The knockdown of key components of unfolded protein response in mitochondria or the endoplasmic reticulum by RNA-interference (RNAi) enhanced paralysis in CL2006 but did not prevent the paralysis reducing activities of quercetin. RNAi for essential members of proteasomal protein degradation or macroautophagy also significantly increased paralysis but prevented quercetin from being effective. Quercetin increased proteasomal activity and, moreover, enhanced the flow of proteins through the macroautophagy pathway as reflected by reduced lysosome staining. The proteostasis network, including unfolded protein response, defines the aggregation of Aβ₁₋₄₂ and the associated paralysis phenotype in a nematode model for Alzheimer's disease. The polyphenol quercetin, by specifically activating macroautophagy and proteasomal degradation pathways, proved able to prevent Aβ₁₋₄₂ agregation and paralysis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

    Directory of Open Access Journals (Sweden)

    Nicholas J Izzo

    Full Text Available Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD. Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

  4. Amyloid beta-mediated epigenetic alteration of insulin-like growth factor binding protein 3 controls cell survival in Alzheimer's disease.

    Science.gov (United States)

    Sung, Hye Youn; Choi, Eun Nam; Lyu, Dahyun; Mook-Jung, Inhee; Ahn, Jung-Hyuck

    2014-01-01

    Swedish double mutation (KM670/671NL) of amyloid precursor protein (APP) is reported to increase toxic amyloid β (Aβ) production via aberrant cleavage at the β-secretase site and thereby cause early-onset Alzheimer's disease (AD). However, the underlying molecular mechanisms leading to AD pathogenesis remains largely unknown. Previously, our transcriptome sequence analyses revealed global expressional modifications of over 600 genes in APP-Swedish mutant-expressing H4 (H4-sw) cells compared to wild type H4 cells. Insulin-like growth factor binding protein 3 (IGFBP3) is one gene that showed significantly decreased mRNA expression in H4-sw cells. In this study, we investigated the functional role of IGFBP3 in AD pathogenesis and elucidated the mechanisms regulating its expression. We observed decreased IGFBP3 expression in the H4-sw cell line as well as the hippocampus of AD model transgenic mice. Treatment with exogenous IGFBP3 protein inhibited Aβ1-42- induced cell death and caspase-3 activity, whereas siRNA-mediated suppression of IGFBP3 expression induced cell death and caspase-3 cleavage. In primary hippocampal neurons, administration of IGFBP3 protein blocked apoptotic cell death due to Aβ1-42 toxicity. These data implicate a protective role for IGFBP3 against Aβ1-42-mediated apoptosis. Next, we investigated the regulatory mechanisms of IGFBP3 expression in AD pathogenesis. We observed abnormal IGFBP3 hypermethylation within the promoter CpG island in H4-sw cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored IGFBP3 expression at both the mRNA and protein levels. Chronic exposure to Aβ1-42 induced IGFBP3 hypermethylation at CpGs, particularly at loci -164 and -173, and subsequently suppressed IGFBP3 expression. Therefore, we demonstrate that expression of anti-apoptotic IGFBP3 is regulated by epigenetic DNA methylation, suggesting a mechanism that contributes to AD pathogenesis.

  5. The effects of Tabernaemontana divaricata root extract on amyloid beta-peptide 25-35 peptides induced cognitive deficits in mice.

    Science.gov (United States)

    Nakdook, Walika; Khongsombat, Onrawee; Taepavarapruk, Pornnarin; Taepavarapruk, Niwat; Ingkaninan, Kornkanok

    2010-07-06

    ETHNOPHAMACOLOGICAL RELEVANCE: Tabernaemontana divaricata (TD), a Thai medicinal herb, has been widely used as an analgesic, sedative, or a cough syrup. Moreover, it has been used in traditional rejuvenation remedies as for preventing forgetfulness and improving the memory. The present study aimed to determine the effect of TD on Abeta25-35 peptides induced cognitive deficits and acetylcholinesterase activity in mice. Mice were pretreated with TDE (250, 500 and 1,000 mg/kg body weight) for 28 days and then received i.c.v. injection of Abeta25-35 peptides. Cognitive performance was evaluated using the Morris water maze (MWM) and step-down avoidance test. The Ellman's colorimetric method was used to investigate the levels of cortical and hippocampal AChE activity. Abeta25-35 peptides induced the memory impairment and the increased levels of cortical and hippocampal AChE activity. The consumption of TDE significantly improved the memory impairment and attenuated the brain levels of AChE activity induced by Abeta25-35 peptides. These findings suggest that subchronic administration of TDE might prevent the Abeta25-35 peptides induced memory deficits by decreasing the AChE activity level. Therefore TDE could potentially be one of nootropic supplements for those elderly people suffering from dementia such as the AD patients. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  6. Neuroprotective mechanism of Kai Xin San: upregulation of hippocampal insulin-degrading enzyme protein expression and acceleration of amyloid-beta degradation

    Directory of Open Access Journals (Sweden)

    Na Wang

    2017-01-01

    Full Text Available Kai Xin San is a Chinese herbal formula composed of Radix Ginseng , Poria , Radix Polygalae and Acorus Tatarinowii Rhizome . It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β (Aβ-induced cognitive dysfunction and is neuroprotective in vivo , but its precise mechanism remains unclear. Expression of insulin-degrading enzyme (IDE, which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42 (200 μM, 5 μL into the hippocampus and subsequently administered Kai Xin San (0.54 or 1.08 g/kg/d intragastrically for 21 consecutive days. Hematoxylin-eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme-linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.

  7. Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates

    Directory of Open Access Journals (Sweden)

    Sharoar Md

    2012-12-01

    Full Text Available Abstract Background Aggregation of soluble, monomeric β- amyloid (Aβ to oligomeric and then insoluble fibrillar Aβ is a key pathogenic feature in development of Alzheimer’s disease (AD. Increasing evidence suggests that toxicity is linked to diffusible Aβ oligomers, rather than to insoluble fibrils. The use of naturally occurring small molecules for inhibition of Aβ aggregation has recently attracted significant interest for development of effective therapeutic strategies against the disease. A natural polyphenolic flavone, Kaempferol-3-O-rhamnoside (K-3-rh, was utilized to investigate its effects on aggregation and cytotoxic effects of Aβ42 peptide. Several biochemical techniques were used to determine the conformational changes and cytotoxic effect of the peptide in the presence and absence of K-3-rh. Results K-3-rh showed a dose-dependent effect against Aβ42 mediated cytotoxicity. Anti-amyloidogenic properties of K-3-rh were found to be efficient in inhibiting fibrilogenesis and secondary structural transformation of the peptide. The consequence of these inhibitions was the accumulation of oligomeric structural species. The accumulated aggregates were smaller, soluble, non-β-sheet and non-toxic aggregates, compared to preformed toxic Aβ oligomers. K-3-rh was also found to have the remodeling properties of preformed soluble oligomers and fibrils. Both of these conformers were found to remodel into non-toxic aggregates. The results showed that K-3-rh interacts with different Aβ conformers, which affects fibril formation, oligomeric maturation and fibrillar stabilization. Conclusion K-3-rh is an efficient molecule to hinder the self assembly and to abrogate the cytotoxic effects of Aβ42 peptide. Hence, K-3-rh and small molecules with similar structure might be considered for therapeutic development against AD.

  8. Obesity and Hepatic Steatosis Are Associated with Elevated Serum Amyloid Beta in Metabolically Stressed APPswe/PS1dE9 Mice.

    Directory of Open Access Journals (Sweden)

    Feng-Shiun Shie

    Full Text Available Diabesity-associated metabolic stresses modulate the development of Alzheimer's disease (AD. For further insights into the underlying mechanisms, we examine whether the genetic background of APPswe/PS1dE9 at the prodromal stage of AD affects peripheral metabolism in the context of diabesity. We characterized APPswe/PS1dE9 transgenic mice treated with a combination of high-fat diet with streptozotocin (HFSTZ in the early stage of AD. HFSTZ-treated APPswe/PS1dE9 transgenic mice exhibited worse metabolic stresses related to diabesity, while serum β-amyloid levels were elevated and hepatic steatosis became apparent. Importantly, two-way analysis of variance shows a significant interaction between HFSTZ and genetic background of AD, indicating that APPswe/PS1dE9 transgenic mice are more vulnerable to HFSTZ treatment. In addition, body weight gain, high hepatic triglyceride, and hyperglycemia were positively associated with serum β-amyloid, as validated by Pearson's correlation analysis. Our data suggests that the interplay between genetic background of AD and HFSTZ-induced metabolic stresses contributes to the development of obesity and hepatic steatosis. Alleviating metabolic stresses including dysglycemia, obesity, and hepatic steatosis could be critical to prevent peripheral β-amyloid accumulation at the early stage of AD.

  9. Interplay Between Age, Cerebral Small Vessel Disease, Parenchymal Amyloid-beta, and Tau Pathology: Longitudinal Studies in Hypertensive Stroke-Prone Rats

    NARCIS (Netherlands)

    Schreiber, S; Drukarch, B.; Garz, C.; Niklass, S.; Stanaszek, L.; Kropf, S.; Bueche, C.; Held, F.; Vielhaber, S.; Attems, J.; Reymann, K.G.; Heinze, H.J.; Carare, R.O.; Wilhelmus, M.M.M.

    2014-01-01

    Background: Accumulation of amyloid-β (Aβ) and hyperphosphorylated tau (ptau) accompany cerebral small vessel disease (CSVD) in the aging brain and in Alzheimer's disease. CSVD is characterized by a heterogeneous spectrum of histopathological features possibly initiated by an endothelial dysfunction

  10. Amyloid beta(1-40-induced astrogliosis and the effect of genistein treatment in rat: a three-dimensional confocal morphometric and proteomic study.

    Directory of Open Access Journals (Sweden)

    Maryam Bagheri

    Full Text Available Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy and proliferation of astrocytes. Here, we performed 3D confocal microscopy to evaluate the morphological response of reactive astrocytes positive for glial fibrillary acidic protein (GFAP in rats, to the presence of Aβ(1-40 in the rat brain before and after treatment with genistein. In 50 astrocytes per animal, we measured the volume and surface area for the nucleus, cell body, the entire cell, the tissue covered by single astrocytes and quantified the number and length of branches, the density of the astrocytes and the intensity of GFAP immunoreactivity. Injecting Aβ(1-40 into the brain of rats caused astrogliosis indicated by increased values for all measured parameters. Mass spectrometric analysis of hippocampal tissue in Aβ(1-40-injected brain showed decreased amounts of tubulins, enolases and myelin basic protein, and increased amounts of dihydropyrimidinase-related protein 2. In Aβ(1-40-injected rats pretreated with genistein, GFAP intensity was decreased to the sham-operated group level, and Aβ(1-40-induced astrogliosis was significantly ameliorated.

  11. Neuroprotective effects of Coptis chinensis Franch polysaccharide on amyloid-beta (Aβ)-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer's disease (AD).

    Science.gov (United States)

    Li, Yujuan; Guan, Shuwen; Liu, Cong; Chen, Xinhua; Zhu, Yuemei; Xie, Yutong; Wang, Jianbin; Ji, Xue; Li, Liqin; Li, Zhuohan; Zhang, Yue; Zeng, Xiangzhi; Li, Mingquan

    2018-03-07

    This study aims to investigate the neuroprotective effects of Coptis chinensis Franch polysaccharide (CCP) on Aβ 1-42 transgenic CL4176 Caenorhabditis elegans, as well as its mechanism of action. The results in life span experiment showed that CCP could significantly increase the lifespan of C. elegans and the effect is in the descending order of 100 mg/L > 500 mg/L > 200 mg/L. The behavioral experiments also demonstrated that CCP at the concentration of 100 mg/L could delay the paralysis rate of C. elegans, which was significantly different from the control group. In terms of Aβ toxicity in C. elegans, morphological observation using Thioflavin S staining method indicated that the deposition of Aβ protein in the head area of the untreated C. elegans was much more than those in the CCP (100 mg/L)-treated CL4176. In line with this finding, fluorogenic quantitative real-time PCR confirmed that the transcriptional levels of HSP16.2 (Y46H3A.D) and HSP16.41 (Y46H3A.E) in C. elegans was 21 times and 79 times higher than those in untreated control. Thus, these data demonstrate that CCP could reduce Aβ-induced toxicity by delaying the aging, decreasing the rate of paralysis, inhibiting the deposition of Aβ, and increasing the expression levels of HSP genes in transgenic C. elegans. Copyright © 2017. Published by Elsevier B.V.

  12. Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons.

    Science.gov (United States)

    Sendrowski, Krzysztof; Sobaniec, Wojciech; Stasiak-Barmuta, Anna; Sobaniec, Piotr; Popko, Janusz

    2015-04-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of β-amyloid (Aβ) peptides in the brain. Deposits of Aβ initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Aβ-injured hippocampal neurons in culture. Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Aβ(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Aβ(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 μM Aβ(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 μM Aβ(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Our results suggest the protective potential of both studied nootropics against Aβ-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  13. Alzheimer's Disease Brain-Derived Amyloid-{beta}-Mediated Inhibition of LTP In Vivo Is Prevented by Immunotargeting Cellular Prion Protein.

    LENUS (Irish Health Repository)

    Barry, Andrew E

    2011-05-18

    Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP(C)), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer\\'s disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo. Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP(C), prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP(C), a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP(C) in mediating synaptic plasticity disruption by soluble Aβ.

  14. Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro

    NARCIS (Netherlands)

    Veerhuis, Robert; van Breemen, Mariëlle J.; Hoozemans, Jeroen M.; Morbin, Michela; Ouladhadj, Jamal; Tagliavini, Fabrizio; Eikelenboom, Piet

    2003-01-01

    Pro-inflammatory cytokines released by activated microglia could be a driving force in Alzheimer's disease (AD) pathology. We evaluated whether the presence of complement factor C1q and serum amyloid P component (SAP) in Abeta deposits is related to microglial activation. Activated microglia

  15. The nicotinic alpha7 acetylcholine receptor agonist ssr180711 is unable to activate limbic neurons in mice overexpressing human amyloid-beta1-42

    DEFF Research Database (Denmark)

    Soderman, A.; Spang-Thomsen, Mogens; Hansen, H.

    2008-01-01

    through the use of co-immunoprecipitation that human Abeta-immunoreactive peptides bind to mice alpha7 nAChR in vivo. Agonists of the alpha7 nAChR improve memory and attentional properties and increase immediate early gene expression in the prefrontal cortex and the nucleus accumbens. We show that acute...

  16. Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex.

    Science.gov (United States)

    Lane, Rachel F; Raines, Summer M; Steele, John W; Ehrlich, Michelle E; Lah, James A; Small, Scott A; Tanzi, Rudolph E; Attie, Alan D; Gandy, Sam

    2010-09-29

    SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer's disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SORCS1 is also genetically associated with types 1 and 2 diabetes mellitus (T1DM, T2DM). We have undertaken a study of the possible role(s) for SorCS1 in metabolism of the Alzheimer's amyloid-β peptide (Aβ) and the Aβ precursor protein (APP), to test the hypothesis that Sorcs1 deficiency might be a common genetic risk factor underlying the predisposition to AD that is associated with T2DM. Overexpression of SorCS1cβ-myc in cultured cells caused a reduction (p = 0.002) in Aβ generation. Conversely, endogenous murine Aβ(40) and Aβ(42) levels were increased (Aβ(40), p = 0.044; Aβ(42), p = 0.007) in the brains of female Sorcs1 hypomorphic mice, possibly paralleling the sexual dimorphism that is characteristic of the genetic associations of SORCS1 with AD and DM. Since SorL1 directly interacts with Vps35 to modulate APP metabolism, we investigated the possibility that SorCS1cβ-myc interacts with APP, SorL1, and/or Vps35. We readily recovered SorCS1:APP, SorCS1:SorL1, and SorCS1:Vps35 complexes from nontransgenic mouse brain. Notably, total Vps35 protein levels were decreased by 49% (p = 0.009) and total SorL1 protein levels were decreased by 29% (p = 0.003) in the brains of female Sorcs1 hypomorphic mice. From these data, we propose that dysfunction of SorCS1 may contribute to both the APP/Aβ disturbance underlying AD and the insulin/glucose disturbance underlying DM.

  17. Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype.

    Directory of Open Access Journals (Sweden)

    Arthur A Nery

    Full Text Available Alzheimer's disease (AD is characterized by brain accumulation of the neurotoxic amyloid-β peptide (Aβ and by loss of cholinergic neurons and nicotinic acetylcholine receptors (nAChRs. Recent evidence indicates that memory loss and cognitive decline in AD correlate better with the amount of soluble Aβ than with the extent of amyloid plaque deposits in affected brains. Inhibition of nAChRs by soluble Aβ40 is suggested to contribute to early cholinergic dysfunction in AD. Using phage display screening, we have previously identified a heptapeptide, termed IQ, homologous to most nAChR subtypes, binding with nanomolar affinity to soluble Aβ40 and blocking Aβ-induced inhibition of carbamylcholine-induced currents in PC12 cells expressing α7 nAChRs. Using alanine scanning mutagenesis and whole-cell current recording, we have now defined the amino acids in IQ essential for reversal of Aβ40 inhibition of carbamylcholine-induced responses in PC12 cells, mediated by α7 subtypes and other endogenously expressed nAChRs. We further investigated the effects of soluble Aβ, IQ and analogues of IQ on α3β4 nAChRs recombinantly expressed in HEK293 cells. Results show that nanomolar concentrations of soluble Aβ40 potently inhibit the function of α3β4 nAChRs, and that subsequent addition of IQ or its analogues does not reverse this effect. However, co-application of IQ makes the inhibition of α3β4 nAChRs by Aβ40 reversible. These findings indicate that Aβ40 inhibits different subtypes of nAChRs by interacting with specific receptor domains homologous to the IQ peptide, suggesting that IQ may be a lead for novel drugs to block the inhibition of cholinergic function in AD.

  18. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

    Science.gov (United States)

    Izzo, Nicholas J; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M

    2014-01-01

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

  19. Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

    Science.gov (United States)

    Izzo, Nicholas J.; Staniszewski, Agnes; To, Lillian; Fa, Mauro; Teich, Andrew F.; Saeed, Faisal; Wostein, Harrison; Walko, Thomas; Vaswani, Anisha; Wardius, Meghan; Syed, Zanobia; Ravenscroft, Jessica; Mozzoni, Kelsie; Silky, Colleen; Rehak, Courtney; Yurko, Raymond; Finn, Patricia; Look, Gary; Rishton, Gilbert; Safferstein, Hank; Miller, Miles; Johanson, Conrad; Stopa, Edward; Windisch, Manfred; Hutter-Paier, Birgit; Shamloo, Mehrdad; Arancio, Ottavio; LeVine, Harry; Catalano, Susan M.

    2014-01-01

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics. PMID:25390368

  20. Regional correlations between [11C]PIB PET and post-mortem burden of amyloid-beta pathology in a diverse neuropathological cohort.

    Science.gov (United States)

    Seo, Sang Won; Ayakta, Nagehan; Grinberg, Lea T; Villeneuve, Sylvia; Lehmann, Manja; Reed, Bruce; DeCarli, Charles; Miller, Bruce L; Rosen, Howard J; Boxer, Adam L; O'Neil, James P; Jin, Lee-Way; Seeley, William W; Jagust, William J; Rabinovici, Gil D

    2017-01-01

    Imaging-pathological correlation studies show that in vivo amyloid-β (Aβ) positron emission tomography (PET) strongly predicts the presence of significant Aβ pathology at autopsy. We sought to determine whether regional PiB-PET uptake would improve sensitivity for amyloid detection in comparison with global measures (experiment 1), and to estimate the relative contributions of different Aβ aggregates to in vivo PET signal (experiment 2). In experiment 1, 54 subjects with [ 11 C] PiB-PET during life and postmortem neuropathologic examination (85.2% with dementia, interval from PET to autopsy 3.1 ± 1.9 years) were included. We assessed Thal amyloid phase (N = 36) and CERAD score (N = 54) versus both global and regional PiB SUVRs. In experiment 2 (N = 42), PiB SUVR and post-mortem amyloid β burden was analyzed in five customized regions of interest matching regions sampled at autopsy. We assessed the relative contribution of neuritic plaques (NPs), diffuse plaques (DPs) and cerebral amyloid angiopathy (CAA) to regional PIB SUVR using multi-linear regression. In experiment 1, there were no differences in Area Under the Curve for amyloid phase ≥ A2 and CERAD score ≥ C2 between global and highest regional PiB SUVR ( p  = 0.186 and 0.230). In experiment 2, when NPs, DPs, and/or CAA were included in the same model, moderate to severe NPs were independently correlated with PiB SUVR in all regions except for the inferior temporal and calcarine ROI (β = 0.414-0.804, p  PiB SUVR in the angular gyrus ROI (β = 0.446, p  = 0.010). CAA was also associated with PiB SUVR in the inferior temporal and calcarine ROI (β = 0.222-0.355, p  PiB-PET SUVR performed as well as regional values for amyloid detection in our cohort. The substrate-specific binding of PiB might differ among the brain specific regions.

  1. Age-related toxicity of amyloid-beta associated with increased pERK and pCREB in primary hippocampal neurons: reversal by blueberry extract

    OpenAIRE

    Brewer, Gregory J.; Torricelli, John R.; Lindsey, Amanda L.; Kunz, Elizabeth Z.; Neuman, A.; Fisher, Derek R.; Joseph, James A.

    2009-01-01

    Further clarification is needed to address the paradox that memory formation, aging and neurodegeneration all involve calcium influx, oxyradical production (ROS) and activation of certain signaling pathways. In aged rats and in APP/PS-1 mice, cognitive and hippocampal Ca2+ dysregulation were reversed by food supplementation with a high antioxidant blueberry extract. Here, we studied whether neurons were an important target of blueberry extract and whether the mechanism involved altered ROS si...

  2. Atorvastatin prevents age-related and amyloid-beta-induced microglial activation by blocking interferon-gamma release from natural killer cells in the brain

    LENUS (Irish Health Repository)

    Lyons, Anthony

    2011-03-31

    Abstract Background Microglial function is modulated by several factors reflecting the numerous receptors expressed on the cell surface, however endogenous factors which contribute to the age-related increase in microglial activation remain largely unknown. One possible factor which may contribute is interferon-γ (IFNγ). IFNγ has been shown to increase in the aged brain and potently activates microglia, although its endogenous cell source in the brain remains unidentified. Methods Male Wistar rats were used to assess the effect of age and amyloid-β (Aβ) on NK cell infiltration into the brain. The effect of the anti-inflammatory compound, atorvastatin was also assessed under these conditions. We measured cytokine and chemokine (IFNγ, IL-2, monocyte chemoattractant protein-1 (MCP-1) and IFNγ-induced protein 10 kDa (IP-10)), expression in the brain by appropriate methods. We also looked at NK cell markers, CD161, NKp30 and NKp46 using flow cytometry and western blot. Results Natural killer (NK) cells are a major source of IFNγ in the periphery and here we report the presence of CD161+ NKp30+ cells and expression of CD161 and NKp46 in the brain of aged and Aβ-treated rats. Furthermore, we demonstrate that isolated CD161+ cells respond to interleukin-2 (IL-2) by releasing IFNγ. Atorvastatin, the HMG-CoA reductase inhibitor, attenuates the increase in CD161 and NKp46 observed in hippocampus of aged and Aβ-treated rats. This was paralleled by a decrease in IFNγ, markers of microglial activation and the chemokines, MCP-1 and IP-10 which are chemotactic for NK cells. Conclusions We propose that NK cells contribute to the age-related and Aβ-induced neuroinflammatory changes and demonstrate that these changes can be modulated by atorvastatin treatment.

  3. Involvement of formyl peptide receptors in receptor for advanced glycation end products (RAGE - and amyloid beta 1-42-induced signal transduction in glial cells

    Directory of Open Access Journals (Sweden)

    Slowik Alexander

    2012-11-01

    Full Text Available Abstract Background Recent studies suggest that the chemotactic G-protein-coupled-receptor (GPCR formyl-peptide-receptor-like-1 (FPRL1 and the receptor-for-advanced-glycation-end-products (RAGE play an important role in the inflammatory response involved in neurodegenerative disorders such as Alzheimer’s disease (AD. Therefore, the expression and co-localisation of mouse formyl peptide receptor (mFPR 1 and 2 as well as RAGE in an APP/PS1 transgenic mouse model using immunofluorescence and real-time RT-PCR were analysed. The involvement of rat or human FPR1/FPRL1 (corresponds to mFPR1/2 and RAGE in amyloid-β 1–42 (Aβ1-42-induced signalling were investigated by extracellular signal regulated kinase 1/2 (ERK1/2 phosphorylation. Furthermore, the cAMP level in primary rat glial cells (microglia and astrocytes and transfected HEK 293 cells was measured. Formyl peptide receptors and RAGE were inhibited by a small synthetic antagonist WRW4 and an inactive receptor variant delta-RAGE, lacking the intracytoplasmatic domains. Results We demonstrated a strong increase of mFPR1/2 and RAGE expression in the cortex and hippocampus of APP/PS1 transgenic mice co-localised to the glial cells. In addition, the Aβ1-42-induced signal transduction is dependant on FPRL1, but also on FPR1. For the first time, we have shown a functional interaction between FPRL1/FPR1 and RAGE in RAGE ligands S100B- or AGE-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition a possible physical interaction between FPRL1 as well as FPR1 and RAGE was shown with co-immunoprecipitation and fluorescence microscopy. Conclusions The results suggest that both formyl peptide receptors play an essential role in Aβ1-42-induced signal transduction in glial cells. The interaction with RAGE could explain the broad ligand spectrum of formyl peptide receptors and their important role for inflammation and the host defence against infections.

  4. Gene expression profiling in the stress control brain region hypothalamic paraventricular nucleus reveals a novel gene network including Amyloid beta Precursor Protein

    Directory of Open Access Journals (Sweden)

    Deussing Jan M

    2010-10-01

    Full Text Available Abstract Background The pivotal role of stress in the precipitation of psychiatric diseases such as depression is generally accepted. This study aims at the identification of genes that are directly or indirectly responding to stress. Inbred mouse strains that had been evidenced to differ in their stress response as well as in their response to antidepressant treatment were chosen for RNA profiling after stress exposure. Gene expression and regulation was determined by microarray analyses and further evaluated by bioinformatics tools including pathway and cluster analyses. Results Forced swimming as acute stressor was applied to C57BL/6J and DBA/2J mice and resulted in sets of regulated genes in the paraventricular nucleus of the hypothalamus (PVN, 4 h or 8 h after stress. Although the expression changes between the mouse strains were quite different, they unfolded in phases over time in both strains. Our search for connections between the regulated genes resulted in potential novel signalling pathways in stress. In particular, Guanine nucleotide binding protein, alpha inhibiting 2 (GNAi2 and Amyloid β (A4 precursor protein (APP were detected as stress-regulated genes, and together with other genes, seem to be integrated into stress-responsive pathways and gene networks in the PVN. Conclusions This search for stress-regulated genes in the PVN revealed its impact on interesting genes (GNAi2 and APP and a novel gene network. In particular the expression of APP in the PVN that is governing stress hormone balance, is of great interest. The reported neuroprotective role of this molecule in the CNS supports the idea that a short acute stress can elicit positive adaptational effects in the brain.

  5. Presence of non-fibrillar amyloid beta protein in skin biopsies of Alzheimer's disease (AD), Down's syndrome and non-AD normal persons

    DEFF Research Database (Denmark)

    Wen, G Y; Wisniewski, H M; Blondal, H

    1994-01-01

    /38 (37%) non-AD control cases. The Fisher exact probability test revealed a significant difference (P = 0.0415 one-tailed) in immunoreactivity between AD and age-matched controls. There was also a significant difference (P = 0.0152 one-tailed; P = 0.0200 two-tailed) between DS and age-matched control...

  6. A high content drug screen identifies ursolic acid as an inhibitor of amyloid beta protein interactions with its receptor CD36.

    Science.gov (United States)

    Wilkinson, Kim; Boyd, Justin D; Glicksman, Marcie; Moore, Kathryn J; El Khoury, Joseph

    2011-10-07

    A pathological hallmark of Alzheimer disease (AD) is deposition of amyloid β (Aβ) in the brain. Aβ binds to microglia via a receptor complex that includes CD36 leading to production of proinflammatory cytokines and neurotoxic reactive oxygen species and subsequent neurodegeneration. Interruption of Aβ binding to CD36 is a potential therapeutic strategy for AD. To identify pharmacologic inhibitors of Aβ binding to CD36, we developed a 384-well plate assay for binding of fluorescently labeled Aβ to Chinese hamster ovary cells stably expressing human CD36 (CHO-CD36) and screened an Food and Drug Administration-approved compound library. The assay was optimized based on the cells' tolerance to dimethyl sulfoxide, Aβ concentration, time required for Aβ binding, reproducibility, and signal-to-background ratio. Using this assay, we identified four compounds as potential inhibitors of Aβ binding to CD36. These compounds were ursolic acid, ellipticine, zoxazolamine, and homomoschatoline. Of these compounds, only ursolic acid, a naturally occurring pentacyclic triterpenoid, successfully inhibited binding of Aβ to CHO-CD36 cells in a dose-dependent manner. The ursolic acid effect reached a plateau at ~20 μm, with a maximal inhibition of 64%. Ursolic acid also blocked binding of Aβ to microglial cells and subsequent ROS production. Our data indicate that cell-based high-content screening of small molecule libraries for their ability to block binding of Aβ to its receptors is a useful tool to identify novel inhibitors of receptors involved in AD pathogenesis. Our data also suggest that ursolic acid is a potential therapeutic agent for AD via its ability to block Aβ-CD36 interactions.

  7. Interaction of the molecular chaperone DNAJB6 with growing amyloid-beta 42 (Aβ42) aggregates leads to sub-stoichiometric inhibition of amyloid formation

    NARCIS (Netherlands)

    Månsson, Cecilia; Arosio, Paolo; Hussein, Rasha; Kampinga, Harm H; Hashem, Reem M; Boelens, Wilbert C; Dobson, Christopher M; Knowles, Tuomas P J; Linse, Sara; Emanuelsson, Cecilia

    2014-01-01

    The human molecular chaperone protein DNAJB6 was recently found to inhibit the formation of amyloid fibrils from polyglutamine peptides associated with neurodegenerative disorders such as Huntington's disease. We show in the present study that DNAJB6 also inhibits amyloid formation by an even more

  8. Chronic treatment with amyloid beta(1-42) inhibits non-cholinergic high-affinity choline transport in NG108-15 cells through protein kinase C signaling

    Czech Academy of Sciences Publication Activity Database

    Nováková, Jana; Mikasová, Lenka; Machová, Eva; Lisá, Věra; Doležal, Vladimír

    2005-01-01

    Roč. 1062, č. 1-2 (2005), s. 101-110 ISSN 0006-8993 R&D Projects: GA AV ČR(CZ) IAA5011206; GA MŠk(CZ) LC554 Grant - others:Lipidiet(XE) QLK1-CT-2002-00172 Institutional research plan: CEZ:AV0Z50110509 Keywords : choline transporter * beta-amyloid * protein kinase C Subject RIV: ED - Physiology Impact factor: 2.296, year: 2005

  9. Proposal for novel curcumin derivatives as potent inhibitors against Alzheimer's disease: Ab initio molecular simulations on the specific interactions between amyloid-beta peptide and curcumin

    Science.gov (United States)

    Ota, Shintaro; Fujimori, Mitsuki; Ishimura, Hiromi; Shulga, Sergiy; Kurita, Noriyuki

    2017-10-01

    Accumulation of amyloid-β (Aβ) peptides in a brain is closely related with the pathogenesis of Alzheimer's disease. To suppress the production of Aβ peptides, we propose novel curcumin derivatives and investigate their binding properties with the amyloid precursor protein (APP), using protein-ligand docking as well as ab initio molecular simulations. Our proposed derivative (curcumin XIV) is found to have a large binding energy with APP and interacts strongly with the cleavage site Ala19 by secretase. It is thus expected that curcumin XIV can protect APP from the secretase attack and be a potent inhibitor against the production of Aβ peptides.

  10. Mutation-based structural modification and dynamics study of amyloid beta peptide (1–42: An in-silico-based analysis to cognize the mechanism of aggregation

    Directory of Open Access Journals (Sweden)

    Pritam Kumar Panda

    2016-03-01

    Full Text Available Alzheimer's disease is the prevalent cause of premature senility, a progressive mental disorder due to degeneration in brain and deposition of amyloid β peptide (1–42, a misfolded protein in the form of aggregation that prevails for a prolonged time and obstructs every aspect of life. One of the primary hallmarks of the neuropathological disease is the accretion of amyloid β peptide in the brain that leads to Alzheimer's disease, but the mechanism is still a mystery. Several investigations have shown that mutations at specific positions have a significant impact in stability of the peptide as predicted from aggregation profiles. Here in our study, we have analyzed the mutations by substituting residues at position A22G, E22G, E22K, E22Q, D23N, L34V and molecular dynamics have been performed to check the deviation in stability and conformation of the peptide. The results validated that the mutations at specific positions lead to instability and the proline substitution at E22P and L34P stalled the aggregation of the peptide. Keywords: Amyloid β peptide, Alzheimer's disease, Aggregation, Mutational analysis, NAMD, UCSF Chimera, Discovery Studio Visualizer

  11. Computational Lower Bounds Using Diagonalization

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 14; Issue 7. Computational Lower Bounds Using Diagonalization - Languages, Turing Machines and Complexity Classes. M V Panduranga Rao. General Article Volume 14 Issue 7 July 2009 pp 682-690 ...

  12. Energy policy of Lower Saxony

    International Nuclear Information System (INIS)

    Hirche, W.

    1988-01-01

    The government of the Land Lower Saxony in February 1988 submitted a new energy programme intended to define the energy-political boundary data for energy industry and energy consumers, and to bring about the broadest possible consensus for the implementation of this energy policy between politicians, the energy industry and the population. The Minister of Economy of Lower Saxony in his statement refers particularly to the topics nuclear energy and coal, renewable energies, structure of areas to be supplied with energy, and considerations relating to a revision of the antitrust laws. (orig.) [de

  13. Lowering the first ATLAS toroid

    CERN Document Server

    Maximilien Brice

    2004-01-01

    The ATLAS detector on the LHC at CERN will consist of eight toroid magnets, the first of which was lowered into the cavern in these images on 26 October 2004. The coils are supported on platforms where they will be attached to form a giant torus. The platforms will hold about 300 tonnes of ATLAS' muon chambers and will envelop the inner detectors.

  14. Expected utility with lower probabilities

    DEFF Research Database (Denmark)

    Hendon, Ebbe; Jacobsen, Hans Jørgen; Sloth, Birgitte

    1994-01-01

    An uncertain and not just risky situation may be modeled using so-called belief functions assigning lower probabilities to subsets of outcomes. In this article we extend the von Neumann-Morgenstern expected utility theory from probability measures to belief functions. We use this theory...

  15. Rhinosinusitis and the lower airways

    NARCIS (Netherlands)

    Hellings, Peter W.; Hens, Greet

    2009-01-01

    The interaction between upper and lower airway disease has been recognized for centuries, with recent studies showing a direct link between upper and airway inflammation in allergic patients. The mechanisms underlying the interaction between nasal and bronchial inflammation have primarily been

  16. Slavery in the Lower South.

    Science.gov (United States)

    Landers, Jane

    2003-01-01

    Provides a detailed account of slave history within the Lower South region of the colonial United States. Focuses on the experiences of Africans in the colonies. Explores the role of the English, Spanish, and French in establishing slavery within the future United States. Addresses the systems of slavery used and treatment of the Africans. (CMK)

  17. Lower-limb venous thrombosis

    African Journals Online (AJOL)

    muscle strains, tears, or twisting injuries to the leg. • other causes of lower-limb swelling such as cardiac, hepatic and renal pathologies. • lymphoedema. • chronic venous hypertension and its complications. • popliteal (Baker's) cysts. • cellulitis. • other knee pathologies. The objective methods of making a diagnosis of DVT ...

  18. Adolescent Neuroblastoma of Lower Limb

    Directory of Open Access Journals (Sweden)

    Rajeshwari K

    2013-04-01

    Full Text Available Neuroblastoma is an embryonic tumour of neural crest origin, commonly seen in children with upper abdomen involvement. Rarely neuroblastomas present in adolescents and adults involving lower limb. Histopathologically neuroblastoma of lower limb can be confused with other small round cell tumour especially with Ewing's sarcoma and rhabdomyosarcoma. A 16 year old male presented with 15x11cm swelling, pain and multiple discharging sinuses of right leg since 4 months. Routine haematological and biochemical analysis were within normal limits. Radiology of right leg showed large soft tissue swelling encompassing the pathological fracture of tibia and bowing of fibula. Fine needle aspiration of the swelling revealed malignant small round cell tumour. Histopathology revealed poorly differentiated neuroblastoma of lower limb. The immunohistochemistry of Synaptophysin and Chromogranin were positive and CD 99 was negative. Neuroblastoma diagnosed at unusual site with uncommon age has poor prognosis. Hence, one must keep in mind the differential diagnosis of neuroblastoma as one of the differential diagnosis in evaluating the soft tissue tumours of lower limb.

  19. MR angiography of lower extremity

    International Nuclear Information System (INIS)

    Fujikawa, Takao

    1991-01-01

    MR angiography by ECG-gated 2D rephase-dephase subtraction method was performed in normal volunteers (n=14) and patients with arterial or venous vascular disease of lower extremities (n=36). Results were compared to digital subtraction angiography or conventional film angiography. In normal cases, superficial femoral and popliteal arteries were well demonstrated by angiography whereas visualization of intrapelvic portion of the arteries was often impaired by mortion artifacts from bowel loops. Diagnostic results of MR angiography and digital or conventional angiography were in agreement in 92.3% of obstructive arteriosclerotic disease, 87.0% of post by-pass graft surgery, and 85.7% of cases in which deep vein thrombosis was clinically suspected. Considering its virtually noninvasive nature, MR angiography can be a valuable screening method in vascular diseases of lower extremities and also in post operative evaluation of by-pass graft surgery. Further technical advancements are expected. (author)

  20. MR angiography of lower extremity

    Energy Technology Data Exchange (ETDEWEB)

    Fujikawa, Takao (Kyorin Univ., Mitaka, Tokyo (Japan). School of Medicine)

    1991-02-01

    MR angiography by ECG-gated 2D rephase-dephase subtraction method was performed in normal volunteers (n=14) and patients with arterial or venous vascular disease of lower extremities (n=36). Results were compared to digital subtraction angiography or conventional film angiography. In normal cases, superficial femoral and popliteal arteries were well demonstrated by angiography whereas visualization of intrapelvic portion of the arteries was often impaired by mortion artifacts from bowel loops. Diagnostic results of MR angiography and digital or conventional angiography were in agreement in 92.3% of obstructive arteriosclerotic disease, 87.0% of post by-pass graft surgery, and 85.7% of cases in which deep vein thrombosis was clinically suspected. Considering its virtually noninvasive nature, MR angiography can be a valuable screening method in vascular diseases of lower extremities and also in post operative evaluation of by-pass graft surgery. Further technical advancements are expected. (author).

  1. Angioleiomyoma of the Lower Leg.

    Science.gov (United States)

    Sprinkle, Robert L B; Sangueza, Omar P; Wells, Ashleigh E

    2017-05-01

    Angioleiomyomas are benign tumefactions that originate from smooth muscle in vascular structures and are difficult to definitively diagnose preoperatively. Although these lesions are rarely encountered in the foot, the lower extremity is the most common site of occurrence. An angioleiomyoma typically manifests as a small, painful, solitary, mobile lesion. This case report describes a lateral retromalleolar para-Achilles tendon insertional location for a moderately sized immobile solid tumefaction in the subcutaneous tissues. The lesion was nonpainful and progressively enlarged over 5 years. An excisional biopsy was performed, and the nodular lesion was subsequently diagnosed histopathologically as an angioleiomyoma. Owing to the ambiguous nature of the clinical findings, angioleiomyoma should be included in the differential diagnosis of lower-extremity soft-tissue manifestations.

  2. Lymphoscintigraphy of the lower extremity

    International Nuclear Information System (INIS)

    Abbasi, N.Z.

    1990-01-01

    Fifty one lower extremities of 26 normal healthy volunteers and 26 extremities of 13 patients with oedema have been studied. Dynamic quantitative lymphoscintigraphy using 99Tc-m antimony sulphide colloid during passive exercise as well as before and after active exercise was performed. parameters of lymphatic function including percentage of radioactivity cleared from the injection site, the percentage uptake by the inguinal lymph nodes, the time of arrival of activity at the regional lymph nodes and the lymphatic reserve index have been evaluated. The percentage clearance of activity from the injection site was found technically difficult to standardize and proved to be an unreliable parameter of lymphatic function. However, the quantitation of nodal uptake, the lymphatic transit time and the lymphatic reserve capacity accurately depicted the lymphatic functional status of an individual. The physiologic parameters of lymphatic function of the contralateral lower extremities were compared and a physiologic difference in the lymphatic capacity of the two limbs was scintigraphically documented. (author)

  3. An Optimal Lower Eigenvalue System

    Directory of Open Access Journals (Sweden)

    Yingfan Liu

    2011-01-01

    Full Text Available An optimal lower eigenvalue system is studied, and main theorems including a series of necessary and suffcient conditions concerning existence and a Lipschitz continuity result concerning stability are obtained. As applications, solvability results to some von-Neumann-type input-output inequalities, growth, and optimal growth factors, as well as Leontief-type balanced and optimal balanced growth paths, are also gotten.

  4. Lower genitourinary infections in women.

    Science.gov (United States)

    Berg, A O; Soman, M P

    1986-07-01

    Vaginitis, cystitis, urethritis, and cervicitis are common diagnoses made in women attending family physicians' offices. Recent research has fundamentally altered available information on the diagnosis and management of these common genitourinary infections. This clinical review discusses presenting symptoms, physical findings, laboratory diagnostic aids, treatment, and follow-up for each lower genitourinary syndrome in women concluding with a summary flow chart illustrating an overall recommended approach.

  5. Lower Mortality in Magnet Hospitals

    Science.gov (United States)

    McHugh, Matthew D.; Kelly, Lesly A.; Smith, Herbert L.; Wu, Evan S.; Vanak, Jill M.; Aiken, Linda H.

    2014-01-01

    Background Although there is evidence that hospitals recognized for nursing excellence—Magnet hospitals—are successful in attracting and retaining nurses, it is uncertain whether Magnet recognition is associated with better patient outcomes than non-Magnets, and if so why. Objectives To determine whether Magnet hospitals have lower risk-adjusted mortality and failure-to-rescue compared with non-Magnet hospitals, and to determine the most likely explanations. Method and Study Design Analysis of linked patient, nurse, and hospital data on 56 Magnet and 508 non-Magnet hospitals. Logistic regression models were used to estimate differences in the odds of mortality and failure-to-rescue for surgical patients treated in Magnet versus non-Magnet hospitals, and to determine the extent to which differences in outcomes can be explained by nursing after accounting for patient and hospital differences. Results Magnet hospitals had significantly better work environments and higher proportions of nurses with bachelor's degrees and specialty certification. These nursing factors explained much of the Magnet hospital effect on patient outcomes. However, patients treated in Magnet hospitals had 14% lower odds of mortality (odds ratio 0.86; 95% confidence interval, 0.76–0.98; P = 0.02) and 12% lower odds of failure-to-rescue (odds ratio 0.88; 95% confidence interval, 0.77–1.01; P = 0.07) while controlling for nursing factors as well as hospital and patient differences. Conclusions The lower mortality we find in Magnet hospitals is largely attributable to measured nursing characteristics but there is a mortality advantage above and beyond what we could measure. Magnet recognition identifies existing quality and stimulates further positive organizational behavior that improves patient outcomes. PMID:24022082

  6. Synthesis of Zirconium Lower Chlorides

    International Nuclear Information System (INIS)

    Gaviria, Juan P.

    2002-01-01

    This research is accurately related to the Halox concept of research reactor spent fuel element treatment.The aim of this project is to work the conditioning through selected chlorination of the element that make the spent fuel element. This research studied the physical chemistry conditions which produce formation of the lower zirconium chlorides through the reaction between metallic Zr and gaseous ZrCl 4 in a silica reactor.This work focused special attention in the analysis and confrontation of the published results among the different authors in order to reveal coincidences and contradictions.Experimental section consisted in a set of synthesis with different reaction conditions and reactor design. After reaction were analyzed the products on Zr shavings and the deposit growth on wall reactor.The products were strongly dependent of reactor design. It was observed that as the distance between Zr and wall reactor increased greater was tendency to lower chlorides formation.In reactors with small distance the reaction follows other way without formation of lower chlorides.Analysis on deposit growth on reactor showed that may be formed to a mixture of Si x Zr y intermetallics and zirconium oxides.Presence of oxygen in Zr and Zr-Si compounds on wall reactor reveals that there is an interaction between quartz and reactants.This interaction is in gaseous phase because contamination is observed in experiences where Zr was not in contact with reactor.Finally, it was made a global analysis of all experiences and a possible mechanism that interprets reaction ways is proposed

  7. Does Wrongful Conviction Lower Deterrence?

    DEFF Research Database (Denmark)

    Lando, Henrik

    2004-01-01

    Does wrongful conviction lower deterrence and can this explain society's aversion tosanctioning the innocent? This paper argues that for some of the most importantcategories of crime such as murder, assault or robbery, the answer to both questions isno. For these categories of crime, a potential...... offender need not fear wrongfulconviction for any particular criminal act he or she chooses not to commit. Forexample, if a potential offender decides not to murder another person, he or sheshould not fear being wrongfully convicted of it, since the person will not be dead,and there will therefore...

  8. Adenomatoid hyperplasia of lower lip

    Directory of Open Access Journals (Sweden)

    Gaganjot Kaur Sharma

    2011-01-01

    Full Text Available Adenomatoid hyperplasia (AH is an uncommon, non-neoplastic swelling on the palate caused due to hyperplasia of the mucinous acini. The lesion clinically presents as a sessile tumor-like nodule resembling pleomorphic adenoma. Histopathologic findings include lobules of enlarged mucinous acini which are filled with secretory granules. The nuclei are squeezed to the basal portions, associated with focal inflammation and ductal dilatation, and a history of trauma is often elicited. Here, we report a rare case of AH of the lower lip in a 20-year-old male patient, which mimics a mucous retention cyst or mucocele.

  9. Approach to Lower Extremity Edema.

    Science.gov (United States)

    Ratchford, Elizabeth V; Evans, Natalie S

    2017-03-01

    Lower extremity edema is extremely common among patients seen across multiple specialties. The differential diagnosis is broad and ranges from simple dependent edema to more complex conditions such as chronic venous disease and lymphedema. Several key features from the history and physical exam can assist with the diagnosis. Imaging is rarely necessary at the initial visit unless venous thromboembolism is suspected. Treatment is specific to the etiology of the edema, but compression stockings, elevation, exercise, and weight loss remain the cornerstone in most cases.

  10. Nash equilibrium with lower probabilities

    DEFF Research Database (Denmark)

    Groes, Ebbe; Jacobsen, Hans Jørgen; Sloth, Birgitte

    1998-01-01

    We generalize the concept of Nash equilibrium in mixed strategies for strategic form games to allow for ambiguity in the players' expectations. In contrast to other contributions, we model ambiguity by means of so-called lower probability measures or belief functions, which makes it possible...... to distinguish between a player's assessment of ambiguity and his attitude towards ambiguity. We also generalize the concept of trembling hand perfect equilibrium. Finally, we demonstrate that for certain attitudes towards ambiguity it is possible to explain cooperation in the one-shot Prisoner's Dilemma...

  11. Lower Gastrointestinal Bleeding in Children.

    Science.gov (United States)

    Sahn, Benjamin; Bitton, Samuel

    2016-01-01

    This article provides an overview of the evaluation and management of lower gastrointestinal bleeding (LGIB) in children. The common etiologies at different ages are reviewed. Conditions with endoscopic importance for diagnosis or therapy include solitary rectal ulcer syndrome, polyps, vascular lesions, and colonic inflammation and ulceration. Diagnostic modalities for identifying causes of LGIB in children include endoscopy and colonoscopy, cross-sectional and nuclear medicine imaging, video capsule endoscopy, and enteroscopy. Pre-endoscopic preparation and decision-making unique to pediatrics is highlighted. The authors conclude with a summary of current and emerging therapeutic hemostatic techniques that can be used in pediatric patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Lower Sioux Wind Feasibility & Development

    Energy Technology Data Exchange (ETDEWEB)

    Minkel, Darin

    2012-04-01

    This report describes the process and findings of a Wind Energy Feasibility Study (Study) conducted by the Lower Sioux Indian Community (Community). The Community is evaluating the development of a wind energy project located on tribal land. The project scope was to analyze the critical issues in determining advantages and disadvantages of wind development within the Community. This analysis addresses both of the Community's wind energy development objectives: the single turbine project and the Commerical-scale multiple turbine project. The main tasks of the feasibility study are: land use and contraint analysis; wind resource evaluation; utility interconnection analysis; and project structure and economics.

  13. Progress on CMS detector lowering

    CERN Multimedia

    2006-01-01

    It was an amazing engineering challenge - the lowering of the first hugeendcap disc (YE+3) of the CMS detector slowly and carefully 100 metres underground. The spectacular descent took place on 30 November and was documented by a film crew from Reuters news group. The uniquely shaped slice is 16 m high, about 50 cm thick, and weighs 400 tonnes. It is one of 15 sections that make up the complete CMS detector. The solid steel structure of the disc forms part of the magnet return yoke and is equipped on both sides with muon chambers. A special gantry crane lowered the element, with just 20 cm of leeway between the edges of the detector and the walls of the shaft! On 12 December, a further section of the detector (YE+2) containing the cathode strip chamber made the 10-hour journey underground. This piece is 16 m high and weighs 880 tonnes. There are now four sections of the detector in the experimental cavern, with a further 11 to follow. The endcap disc YE+3 (seen in the foreground) begins its journey down the ...

  14. Lower airway papillomatosis in children.

    Science.gov (United States)

    Zawadzka-Głos, Lidia; Jakubowska, Anna; Chmielik, Mieczysław; Bielicka, Anna; Brzewski, Michał

    2003-10-01

    Laryngeal papilloma in children is a frequent disease caused by human papilloma virus (HPV) type 6 or type 11. This disease has a tendency to recur and the changes are histologically benign. In some cases papilloma may affect the lower levels of the respiratory tract. In this study, among 90 patients treated for laryngeal papillomatosis, in four children papilloma of trachea, bronchi and lung tissue were detected in endoscopic and radiological examination. This constitutes 4.4% of all patients. Compact nodules and acquired cysts between 5 and 50 mm long were found in chest X-rays and in computerised tomography. These cysts appeared from 4 to 8 years after establishing a diagnosis of laryngeal papilloma, and 1 year after recognising papilloma in the trachea. In all four children the presence of nodules and cysts in the lungs was preceded by recurrent pneumonia, emphysema or atelectasis of the lungs. All children with laryngeal papillomatosis should have a chest X-ray. Detection of acquired cyst-like changes in lung tissue in children with laryngeal papillomatosis is a warning of future papilloma in the trachea and bronchi, with involvement of lung tissue. In differential diagnosis of these changes in the lungs we should take into consideration the presence of papilloma in the bronchi. A prognosis of papillomatosis in the lower airways in children is always serious.

  15. Overprescribing of lipid lowering agents.

    Science.gov (United States)

    Smith, M A; Cox, E D; Bartell, J M

    2006-08-01

    Undertreatment of hyperlipidemia has received considerable attention. However, little is known about trends in overprescribing of lipid lowering agents. We examined these trends and their associations with physician, practice, and organisational factors. 2034 physicians were surveyed twice: baseline (1996-7) and follow up (1998-9). On each occasion they were asked: "For what percentage of 50 year old men without other cardiac risk factors would you recommend an oral agent for total cholesterol of 240, LDL 150, and HDL 50 after 6 months on a low cholesterol diet?" During the survey period the National Cholesterol Education Program guidelines did not recommend prescribing for these patients. Binomial and multinomial logistic regressions assessed baseline overprescribing and longitudinal changes in overprescribing, accounting for complex sampling. 39% of physicians recommended prescribing at baseline (round 1), increasing at follow up (round 2) to 51% (p overprescribe at baseline were less likely to be board certified (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.38 to 0.63; p overprescribing to be international medical graduates (OR 2.09, 95% CI 1.20 to 3.64; p = 0.011) and to spend more hours in patient care (OR 1.14, 95% CI 1.03 to 1.26; p = 0.016). Overprescribing of lipid lowering agents is commonplace and increased. At baseline and longitudinally, overprescribing was primarily associated with physician and practice characteristics and not with organisational factors.

  16. Differentiating lower motor neuron syndromes.

    Science.gov (United States)

    Garg, Nidhi; Park, Susanna B; Vucic, Steve; Yiannikas, Con; Spies, Judy; Howells, James; Huynh, William; Matamala, José M; Krishnan, Arun V; Pollard, John D; Cornblath, David R; Reilly, Mary M; Kiernan, Matthew C

    2017-06-01

    Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Lower-hybrid wave collapse

    International Nuclear Information System (INIS)

    Robinson, P.A.; Melatos, A.; Rozmus, W.

    1996-01-01

    The formation, collapse and arrest of lower-hybrid wave packets are investigated analytically. The three-dimensional structure of the wave packet is incorporated in the analysis and its polarization is studied for the first time. Nonlinear collapse thresholds are obtained via a Hamiltonian formulation and are used in calculating the probability distribution of collapsing wave packet structures as a function of their polarization. Transit-time interaction theory is then used to calculate the arrest scale at which collapse is halted as the waves are damped. It is found that collapse thresholds are lowest for circularly polarized packets, but that nearly linearly polarized ones predominate in collapse because of their greater numbers in the linear phase of the evolution. It is argued that subsonic collapse persists until very near arrest, in accord with recent numerical simulations. Time scale analysis shows that the parallel field structure has difficulty in attaining its self-similar form in the available collapse time, also in accord with simulations. Transit-time theory implies that electrons travelling roughly parallel to the ambient magnetic field can arrest collapse at a scale comparable to that previously estimated for ions; which process dominates depends on the electron and ion temperatures and packet geometry. The resulting arrest scales are found to be in accord with the simulations. copyright 1996 American Institute of Physics

  18. Chemical defense lowers plant competitiveness.

    Science.gov (United States)

    Ballhorn, Daniel J; Godschalx, Adrienne L; Smart, Savannah M; Kautz, Stefanie; Schädler, Martin

    2014-11-01

    Both plant competition and plant defense affect biodiversity and food web dynamics and are central themes in ecology research. The evolutionary pressures determining plant allocation toward defense or competition are not well understood. According to the growth-differentiation balance hypothesis (GDB), the relative importance of herbivory and competition have led to the evolution of plant allocation patterns, with herbivore pressure leading to increased differentiated tissues (defensive traits), and competition pressure leading to resource investment towards cellular division and elongation (growth-related traits). Here, we tested the GDB hypothesis by assessing the competitive response of lima bean (Phaseolus lunatus) plants with quantitatively different levels of cyanogenesis-a constitutive direct, nitrogen-based defense against herbivores. We used high (HC) and low cyanogenic (LC) genotypes in different competition treatments (intra-genotypic, inter-genotypic, interspecific), and in the presence or absence of insect herbivores (Mexican bean beetle, Epilachna varivestis) to quantify vegetative and generative plant parameters (above and belowground biomass as well as seed production). Highly defended HC-plants had significantly lower aboveground biomass and seed production than LC-plants when grown in the absence of herbivores implying significant intrinsic costs of plant cyanogenesis. However, the reduced performance of HC- compared to LC-plants was mitigated in the presence of herbivores. The two plant genotypes exhibited fundamentally different responses to various stresses (competition, herbivory). Our study supports the GDB hypothesis by demonstrating that competition and herbivory affect different plant genotypes differentially and contributes to understanding the causes of variation in defense within a single plant species.

  19. DASH diet to lower high blood pressure

    Science.gov (United States)

    ... ency/patientinstructions/000770.htm DASH diet to lower high blood pressure To use the sharing features on this page, ... JavaScript. DASH stands for Dietary Approaches to Stop Hypertension. The DASH diet can help lower high blood ...

  20. Ellagic acid ameliorates learning and memory deficits in a rat model of Alzheimer's disease: an exploration of underlying mechanisms.

    Science.gov (United States)

    Kiasalari, Zahra; Heydarifard, Rana; Khalili, Mohsen; Afshin-Majd, Siamak; Baluchnejadmojarad, Tourandokht; Zahedi, Elham; Sanaierad, Ashkan; Roghani, Mehrdad

    2017-06-01

    Alzheimer's disease (AD) is a neurodegenerative disorder with irreversible loss of intellectual abilities. Current therapies for AD are still insufficient. In this study, the effect of ellagic acid on learning and memory deficits was evaluated in intrahippocampal amyloid beta (Aβ 25-35 )-microinjected rats and its modes of action were also explored. AD rat model was induced by bilateral intrahippocampal microinjection of Aβ 25-35 and ellagic acid was daily administered (10, 50, and 100 mg/kg), and learning, recognition memory, and spatial memory were evaluated in addition to histochemical assessment, oxidative stress, cholinesterases activity, and level of nuclear factor-kappaB (NF-κB), Toll-like receptor 4 (TLR4), and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The amyloid beta-microinjected rats showed a lower discrimination ratio in novel object and alternation score in Y maze tasks and exhibited an impairment of retention and recall capability in passive avoidance paradigm and higher working and reference memory errors in radial arm maze (RAM). In addition, amyloid beta group showed a lower number of Nissl-stained neurons in CA1 area in addition to enhanced oxidative stress, higher activity of cholinesterases, greater level of NF-κB and TLR4, and lower level of nuclear/cytoplasmic ratio for Nrf2 and ellagic acid at a dose of 100 mg/kg significantly prevented most of these abnormal alterations. Ellagic acid pretreatment of intrahippocampal amyloid beta-microinjected rats could dose-dependently improve learning and memory deficits via neuronal protection and at molecular level through mitigation of oxidative stress and acetylcholinesterase (AChE) activity and modulation of NF-κB/Nrf2/TLR4 signaling pathway.

  1. Prevention of Lower Extremity Injuries in Basketball

    OpenAIRE

    Taylor, Jeffrey B.; Ford, Kevin R.; Nguyen, Anh-Dung; Terry, Lauren N.; Hegedus, Eric J.

    2015-01-01

    Context: Lower extremity injuries are common in basketball, yet it is unclear how prophylactic interventions affect lower extremity injury incidence rates. Objective: To analyze the effectiveness of current lower extremity injury prevention programs in basketball athletes, focusing on injury rates of (1) general lower extremity injuries, (2) ankle sprains, and (3) anterior cruciate ligament (ACL) tears. Data Sources: PubMed, MEDLINE, CINAHL, SPORTDiscus, and the Cochrane Register of Controlle...

  2. Validated assessment scales for the lower face.

    Science.gov (United States)

    Narins, Rhoda S; Carruthers, Jean; Flynn, Timothy C; Geister, Thorin L; Görtelmeyer, Roman; Hardas, Bhushan; Himmrich, Silvia; Jones, Derek; Kerscher, Martina; de Maio, Maurício; Mohrmann, Cornelia; Pooth, Rainer; Rzany, Berthold; Sattler, Gerhard; Buchner, Larry; Benter, Ursula; Breitscheidel, Lusine; Carruthers, Alastair

    2012-02-01

    Aging in the lower face leads to lines, wrinkles, depression of the corners of the mouth, and changes in lip volume and lip shape, with increased sagging of the skin of the jawline. Refined, easy-to-use, validated, objective standards assessing the severity of these changes are required in clinical research and practice. To establish the reliability of eight lower face scales assessing nasolabial folds, marionette lines, upper and lower lip fullness, lip wrinkles (at rest and dynamic), the oral commissure and jawline, aesthetic areas, and the lower face unit. Four 5-point rating scales were developed to objectively assess upper and lower lip wrinkles, oral commissures, and the jawline. Twelve experts rated identical lower face photographs of 50 subjects in two separate rating cycles using eight 5-point scales. Inter- and intrarater reliability of responses was assessed. Interrater reliability was substantial or almost perfect for all lower face scales, aesthetic areas, and the lower face unit. Intrarater reliability was high for all scales, areas and the lower face unit. Our rating scales are reliable tools for valid and reproducible assessment of the aging process in lower face areas. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.

  3. Powering of lower extremities in fitness centre

    OpenAIRE

    Zavičák, Ondřej

    2011-01-01

    Title: Strengthening of the lower limbs in fitness center. Objectives: The aim of thesis is to create an overview for strengthening the legs in fitness and for people who have decided to devote this strengthening. Methods: The paper has been used the literature analysis and interviews. Target group interviews were 20 women and 20 men who attend fitness center. Results: In this work it was found that women strengthen the lower limbs more often and longer than men. The lower limbs are overwhelm...

  4. Lower mesiodens: report of an unusual case.

    Science.gov (United States)

    Alencar, Marilia; Duarte, Danilo; Cury, Patricia; Bönecker, Marcelo

    2005-01-01

    This report describes a case of an 11 years old girl presenting a supernumerary tooth between lower central incisors. The case initially required only surgical treatment to remove the lower mesiodens. Sequentially, the patient was referred to an orthodontic therapy due to a presence of diastema.

  5. Characteristics of the Russian Lower Class

    Science.gov (United States)

    Tikhonova, N. E.

    2011-01-01

    Lower socioeconomic strata in Russia have their origins in both the former Soviet lower strata and economic decline of the 1990s. Part of the reason for their persistence is the geographic mismatch between jobs and the labor supply, in addition to lack of education, skills, and social support. The situation cannot be solved by just providing…

  6. Lower internals for pressurized water reactor

    International Nuclear Information System (INIS)

    Chevereau, G.; Babin, M.

    1989-01-01

    The lower internals for PWR has a separating plate mounted beneath its lower core plate and defining a distribution chamber with it, peripheral mechanical connectors joining the plates separated by coolant passage and apertures in the separation plate connected to a coolant pipe [fr

  7. The spectrum of lower motor neuron syndromes

    NARCIS (Netherlands)

    van den Berg-Vos, R. M.; van den Berg, L. H.; Visser, J.; de Visser, M.; Franssen, H.; Wokke, J. H. J.

    2003-01-01

    This review discusses the most important lower motor neuron syndromes. This relatively rare group of syndromes has not been well described clinically. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) are primarily affected or motor axons and

  8. Stacked spheres and lower bound theorem

    Indian Academy of Sciences (India)

    BASUDEB DATTA

    2011-11-20

    Nov 20, 2011 ... Preliminaries. Lower bound theorem. On going work. Definitions. An n-simplex is a convex hull of n + 1 affinely independent points. (called vertices) in some Euclidean space R. N . Stacked spheres and lower bound theorem. Basudeb Datta. Indian Institute of Science. 2 / 27 ...

  9. Bringing the Humanities to the Lower Achiever.

    Science.gov (United States)

    Ross, Kathleen

    1989-01-01

    Describes a humanities program for senior high school basic classes. Notes that the course covers Greek drama, poetry, art, classical music, and Shakespearean plays. Asserts that giving lower-ability students a chance to study the classics makes them feel less alienated from the mainstream. (MM)

  10. Exponential Lower Bounds For Policy Iteration

    OpenAIRE

    Fearnley, John

    2010-01-01

    We study policy iteration for infinite-horizon Markov decision processes. It has recently been shown policy iteration style algorithms have exponential lower bounds in a two player game setting. We extend these lower bounds to Markov decision processes with the total reward and average-reward optimality criteria.

  11. Giant lower oesophageal ulcer Bushman baby

    African Journals Online (AJOL)

    1983-02-26

    Feb 26, 1983 ... Giant lower oesophageal ulcer. Bushman baby. A case report. J. J. HEYDENRYCH, A. D. KEET. •. ID a. Summary. The case of a giant, penetrating lower oesophageal ulcer in a 14-month-old Bushman baby is reported. ... crying precluded a thorough systematic examination. Food was immediately rejected.

  12. Frailty and Lower Urinary Tract Symptoms.

    Science.gov (United States)

    Suskind, Anne M

    2017-09-01

    The incidence of both frailty and lower urinary tract symptoms, including urinary incontinence, overactive bladder, underactive bladder, and benign prostatic hyperplasia, increases with age. However, our understanding of the relationship between frailty and lower urinary tract symptoms, both in terms of pathophysiology and in terms of the evaluation and management of such symptoms, is greatly lacking. This brief review will summarize definitions and measurement tools associated with frailty and will also review the existing state of the literature on frailty and lower urinary tract symptoms in older individuals.

  13. Customizable Rehabilitation Lower Limb Exoskeleton System

    Directory of Open Access Journals (Sweden)

    Riaan Stopforth

    2012-10-01

    Full Text Available Disabled people require assistance with the motion of their lower limbs to improve rehabilitation. Exoskeletons used for lower limb rehabilitation are highly priced and are not affordable to the lowerincome sector of the population. This paper describes an exoskeleton lower limb system that was designed keeping in mind that the cost must be as low as possible. The forward kinematic system that is used must be a simplified model to decrease computational time, yet allow the exoskeleton to be adjustable according to the patient's leg dimensions.

  14. Infection in the ischemic lower extremity.

    Science.gov (United States)

    Fry, D E; Marek, J M; Langsfeld, M

    1998-06-01

    Infections in the lower extremity of the patient with ischemia can cover a broad spectrum of different diseases. An understanding of the particular pathophysiologic circumstances in the ischemic extremity can be of great value in understanding the natural history of the disease and the potential complications that may occur. Optimizing blood flow to the extremity by using revascularization techniques is important for any patient with an ischemic lower extremity complicated by infection or ulceration. Infections in the ischemic lower extremity require local débridement and systemic antibiotics. For severe infections, such as necrotizing fasciitis or the fetid foot, more extensive local débridement and even amputation may be required. Fundamentals of managing prosthetic graft infection require removing the infected prosthesis, local wound débridement, and systemic antibiotics while attempting to preserve viability of the lower extremity using autogenous graft reconstruction.

  15. Lower hybrid current drive in shaped tokamaks

    International Nuclear Information System (INIS)

    Kesner, J.

    1993-01-01

    A time dependent lower hybrid current drive tokamak simulation code has been developed. This code combines the BALDUR tokamak simulation code and the Bonoli/Englade lower hybrid current drive code and permits the study of the interaction of lower hybrid current drive with neutral beam heating in shaped cross-section plasmas. The code is time dependent and includes the beam driven and bootstrap currents in addition to the current driven by the lower hybrid system. Examples of simulations are shown for the PBX-M experiment which include the effect of cross section shaping on current drive, ballooning mode stabilization by current profile control and sawtooth stabilization. A critical question in current drive calculations is the radial transport of the energetic electrons. The authors have developed a response function technique to calculate radial transport in the presence of an electric field. The consequences of the combined influences of radial diffusion and electric field acceleration are discussed

  16. Obstacle crossing in lower limb amputees

    NARCIS (Netherlands)

    Vrieling, A.H.; van Keeken, H.G.; Schoppen, Tanneke; Otten, Egbert; Halbertsma, J.P.; Hof, A.L.; Postema, K.

    2007-01-01

    Objective: To study limitations in function and adjustment strategies in lower limb amputees during obstacle crossing. Design: Observational cohort study. Subjects: Transfemoral and transtibial amputees and able-bodied control subjects. Methods: In a motion analysis laboratory unimpeded and obstacle

  17. Gait termination in lower limb amputees

    NARCIS (Netherlands)

    Vrieling, A. H.; van Keeken, H. G.; Schoppen, T.; Otten, E.; Halbertsma, J. P. K.; Hof, A. L.; Postema, K.

    Objective: To study the limitations in function and adjustment strategies of lower limb amputees in gait termination. Design: Observational cohort study. Setting: University Medical Centre. Participants: Unilateral transfemoral and transtibial amputees, and able-bodied control subjects. Main outcome

  18. Lower Saccharide Nanometric Materials and Methods

    Energy Technology Data Exchange (ETDEWEB)

    Schilling, Christopher H.; Tomasik, Piotr; Sikora, Marek

    2004-07-13

    A ceramic composition having at least one nanometric ceramic powder, at least one lower saccharide, and water. The composition is useful in many industrial applications, including preparation of stronger and substantially defect free green and sintered ceramic bodies.

  19. Cranberries and lower urinary tract infection prevention

    Directory of Open Access Journals (Sweden)

    Marcelo Hisano

    2012-01-01

    Full Text Available Lower urinary tract infections are very common diseases. Recurrent urinary tract infections remain challenging to treat because the main treatment option is long-term antibiotic prophylaxis; however, this poses a risk for the emergence of bacterial resistance. Some options to avoid this risk are available, including the use of cranberry products. This article reviews the key methods in using cranberries as a preventive measure for lower urinary tract infections, including in vitro studies and clinical trials.

  20. Prevention of Lower Extremity Injuries in Basketball

    Science.gov (United States)

    Taylor, Jeffrey B.; Ford, Kevin R.; Nguyen, Anh-Dung; Terry, Lauren N.; Hegedus, Eric J.

    2015-01-01

    Context: Lower extremity injuries are common in basketball, yet it is unclear how prophylactic interventions affect lower extremity injury incidence rates. Objective: To analyze the effectiveness of current lower extremity injury prevention programs in basketball athletes, focusing on injury rates of (1) general lower extremity injuries, (2) ankle sprains, and (3) anterior cruciate ligament (ACL) tears. Data Sources: PubMed, MEDLINE, CINAHL, SPORTDiscus, and the Cochrane Register of Controlled Trials were searched in January 2015. Study Selection: Studies were included if they were randomized controlled or prospective cohort trials, contained a population of competitive basketball athletes, and reported lower extremity injury incidence rates specific to basketball players. In total, 426 individual studies were identified. Of these, 9 met the inclusion criteria. One other study was found during a hand search of the literature, resulting in 10 total studies included in this meta-analysis. Study Design: Systematic review and meta-analysis. Level of Evidence: Level 2. Data Extraction: Details of the intervention (eg, neuromuscular vs external support), size of control and intervention groups, and number of injuries in each group were extracted from each study. Injury data were classified into 3 groups based on the anatomic diagnosis reported (general lower extremity injury, ankle sprain, ACL rupture). Results: Meta-analyses were performed independently for each injury classification. Results indicate that prophylactic programs significantly reduced the incidence of general lower extremity injuries (odds ratio [OR], 0.69; 95% CI, 0.57-0.85; P basketball athletes. Conclusion: In basketball players, prophylactic programs may be effective in reducing the risk of general lower extremity injuries and ankle sprains, yet not ACL injuries. PMID:26502412

  1. Ultrasonography of the hip and lower extremity.

    Science.gov (United States)

    Malanga, Gerard A; Dentico, Richard; Halperin, Jonathan S

    2010-08-01

    Musculoskeletal ultrasonographic evaluation of the proximal lower limb includes the evaluation of the soft tissue structures, including tendons, ligaments, or muscles, and the bony structures of this region, include the hip, pubic symphysis, and sacroiliac joints. The evaluation of the hip or proximal lower limb region can be performed in an efficient and systematic manner. Ultrasonography of the lateral hip, intra-articular hip, medial thigh, and posterior thigh are discussed in the article. Copyright 2010 Elsevier Inc. All rights reserved.

  2. Hydropower potential of the lower Vistula

    Directory of Open Access Journals (Sweden)

    Michał Szydłowski

    2015-03-01

    Full Text Available This paper presents an estimate analysis of the hydropower potential of the lower Vistula River from Warsaw to Gdańsk Bay. The calculations were made for a hydraulic model of the lower Vistula which takes into account potential development of barrages in a cascade system. Results obtained from the model simulations and from hydrological calculations were used to estimate the power of hydropower plants and the average annual energy output from the entire cascade system. The results of calculations indicate significant energy benefits resulting from the development of a cascade of hydropower plants in the lower Vistula. This study does not discuss the cascade project’s economic viability or other aspects of its development (inland waterways, flood control, etc..

  3. Upper entropy axioms and lower entropy axioms

    International Nuclear Information System (INIS)

    Guo, Jin-Li; Suo, Qi

    2015-01-01

    The paper suggests the concepts of an upper entropy and a lower entropy. We propose a new axiomatic definition, namely, upper entropy axioms, inspired by axioms of metric spaces, and also formulate lower entropy axioms. We also develop weak upper entropy axioms and weak lower entropy axioms. Their conditions are weaker than those of Shannon–Khinchin axioms and Tsallis axioms, while these conditions are stronger than those of the axiomatics based on the first three Shannon–Khinchin axioms. The subadditivity and strong subadditivity of entropy are obtained in the new axiomatics. Tsallis statistics is a special case of satisfying our axioms. Moreover, different forms of information measures, such as Shannon entropy, Daroczy entropy, Tsallis entropy and other entropies, can be unified under the same axiomatics

  4. Lower Cretaceous Dinosaur Tracks from Puebla, Mexico

    Directory of Open Access Journals (Sweden)

    Rubén A. Rodríguez-de la Rosa

    2012-01-01

    Full Text Available Dinosaur tracks have been identified near San Martín Atexcal, southern Puebla, Mexico, within the sedimentary sequence of the San Juan Raya Formation of Lower Cretaceous (Albian age. The tracksite, located in the bed of the Magdalena River, reveals six different ichnofossiliferous levels identified within a 9 m thick sedimentary sequence. The inferred environment is that of a tidal (marginal marine mudflat (Level I. Level I preserves three theropods trackways (?Allosauroidea, additionally, isolated tracks belonging to iguanodontids (Ornithopoda. Level II preserves faint iguanodontid tracks. Levels III to V preserve sauropod tracks. Younger level VI preserves, although morphologically different, a track belonging to Ornithopoda. The dinosaur tracks from San Martín Atexcal support the existence of continental facies within the San Juan Raya Formation; they represent the second record of dinosaur tracks from the Lower Cretaceous of Mexico and are part of an important but little documented record of Lower Cretaceous dinosaurs in Mexico.

  5. Lower-Conductivity Thermal-Barrier Coatings

    Science.gov (United States)

    Miller, Robert A.; Zhu, Dongming

    2003-01-01

    Thermal-barrier coatings (TBCs) that have both initial and post-exposure thermal conductivities lower than those of yttria-stabilized zirconia TBCs have been developed. TBCs are thin ceramic layers, generally applied by plasma spraying or physical vapor deposition, that are used to insulate air-cooled metallic components from hot gases in gas turbine and other heat engines. Heretofore, yttria-stabilized zirconia (nominally comprising 95.4 atomic percent ZrO2 + 4.6 atomic percent Y2O3) has been the TBC material of choice. The lower-thermal-conductivity TBCs are modified versions of yttria-stabilized zirconia, the modifications consisting primarily in the addition of other oxides that impart microstructural and defect properties that favor lower thermal conductivity.

  6. Lower-Limb Rehabilitation Robot Design

    Science.gov (United States)

    Bouhabba, E. M.; Shafie, A. A.; Khan, M. R.; Ariffin, K.

    2013-12-01

    It is a general assumption that robotics will play an important role in therapy activities within rehabilitation treatment. In the last decade, the interest in the field has grown exponentially mainly due to the initial success of the early systems and the growing demand caused by increasing numbers of stroke patients and their associate rehabilitation costs. As a result, robot therapy systems have been developed worldwide for training of both the upper and lower extremities. This paper investigates and proposes a lower-limb rehabilitation robot that is used to help patients with lower-limb paralysis to improve and resume physical functions. The proposed rehabilitation robot features three rotary joints forced by electric motors providing linear motions. The paper covers mechanism design and optimization, kinematics analysis, trajectory planning, wearable sensors, and the control system design. The design and control system demonstrate that the proposed rehabilitation robot is safe and reliable with the effective design and better kinematic performance.

  7. Hydrological perspectives of the Lower Mekong

    Energy Technology Data Exchange (ETDEWEB)

    Adamson, P. [Halcrow Water, Swindon (United Kingdom)

    2001-03-01

    The development of a reservoir and hydro power cascade on the Lancang Jiang (Upper Mekong) at Yunnan in China will have a major impact on the seasonal cycle of flow in the Lower Mekong in its catchment areas of Laos, Myanmar, Thailand, Cambodia and Vietnam. Seven key sites on the Lower Mekong are identified. The geography of the Mekong catchment area, existing and planned reservoir storage on the Mekong, the proposed Lancang Jiang cascade and the hydrological context are described. The effects on flow regimes of the proposed cascade were studied; details of the predicted percentage changes in mean monthly discharge at the seven key sites are given.

  8. Present state of Tevatron lower temperature operation

    International Nuclear Information System (INIS)

    Norris, B.L.

    1996-09-01

    Fermilab continues to work on raising the particle energy of the Tevatron by lowering magnet temperatures using cold vapor compressors. In 1995, another two rounds of power tests were completed. These power tests, although showing significant improvement over the initial tests of 1993-94, have led to the conclusion that 1000 GeV operation cannot be attained without replacing/rearranging magnets with lower quench currents before the next Collider Run in 1999. Development of more cold compressor control strategies also continues

  9. Lower Hybrid to Whistler Wave Conversion

    Energy Technology Data Exchange (ETDEWEB)

    Winske, Dan [Los Alamos National Laboratory

    2012-07-16

    In this presentation we discuss recent work concerning the conversion of whistler waves to lower hybrid waves (as well as the inverse process). These efforts have been motivated by the issue of attenuation of upward propagating whistler waves in the ionosphere generated by VLF transmitters on the ground, i.e., the 'Starks 20 db' problem, which affects the lifetimes of energetic electrons trapped in the geomagnetic field at low magnetic altitude (L). We discuss recent fluid and kinetic plasma simulations as well as ongoing experiments at UCLA to quantify linear and nonlinear mode conversion of lower hybrid to whistler waves.

  10. Computational Lower Bounds Using Diagonalization-II

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 15; Issue 4. Computational Lower Bounds Using Diagonalization - II. M V Panduranga Rao. General Article Volume 15 Issue 4 April 2010 pp 337-346 ... Keywords. Diagonalization; time–hierarchy theorem; relativization; Baker–Gill–Solovay theorem.

  11. Colonoscopic findings in patients presenting with lower ...

    African Journals Online (AJOL)

    Conclusion: In our practice, haemorrhoids and colonic diverticulosis were the leading causes of LGIB at endoscopy. Colonoscopy is therefore recommended for all patients presenting with LGIB, especially for those who are 50 years and older in age. Keywords: Lower gastrointestinal bleeding, Colonoscopy, Nigeria ...

  12. Botulinum toxin treatment of lower extremity spasticity

    Directory of Open Access Journals (Sweden)

    S. E. Khat’kova

    2017-01-01

    Full Text Available The article reviews the current concept of lower extremity spasticity, which is a frequent disabling consequence of stroke. Gait biomechanics, step cycle and main pathologic patterns of lower extremity are described (hip adduction, knee flexion, knee extension, foot plantar flexion, equinovarus foot position, toes flexion, hallux extension, including muscles involved in the pathological process. Additionally the article contains detailed information on pathologic principles of lower extremity spasticity development. Special focus is given to sarcomeregenesis as an essential element of the development of potential conditions for muscle tissue adaptation to a new state and restoration of muscle length and strength. At present Botulinum toxin A (BTA is used in a complex spasticity management programs. The results of clinical studies performed in the last decade supporting the efficacy of Botox® (Onabotulinumtoxin A in the treatment of spasticity are reviewed. Effective BTA doses are proposed. Authors came to the conclusion that BTA as a part of complex rehabilitation in patients with poststroke spasticity of lower extremity promotes treatment efficacy due to a decrease of muscle tone and increase of range of movements in the joints. BTA should be regarded as an essential part of standard rehabilitation programs. Further studies to define optimal muscles for intervention, BTA doses and rehabilitation schemes are still needed. 

  13. Can hibiscus tea lower blood pressure

    Science.gov (United States)

    Hibiscus sabdariffa is a common ingredient found in blended herbal teas, and beverages made from the dried calyces of this plant are popular worldwide. In vitro studies have shown that H. sabdariffa has antioxidant properties and, in animal models of hypertension, extracts of this plant lower blood ...

  14. [Lower urinary tract dysfunction following radical hysterectomy].

    Science.gov (United States)

    Aoun, F; Roumeguère, T

    2015-12-01

    Radical hysterectomy is associated with a significant amount of urinary functional complications and a negative impact on quality of life. The aim of this review is to provide a comprehensive overview of the neurological etiology of lower urinary tract dysfunction following radical hysterectomy and to establish an optimal postoperative management strategy. We performed a comprehensive overview using the following terms: "radical hysterectomy" and "urologic diseases etiology" or "urologic disease prevention and control". The reported incidence of lower urinary tract dysfunction after radical hysterectomy varies from 12 to 85%. Several animal and clinical urodynamic studies corroborate the neurologic etiology of the dysfunction. Lower urinary tract dysfunction is a common postoperative finding (70-85%) but spontaneous recovery is to be expected within 6-12 months after surgery. The most frequent long term sequela is stress urinary incontinence (40% of cases) and its management is complex and challenging. Postoperative refractory overactive bladder and bladder underactivity can be treated by neuromodulation of sacral roots and superior hypogastric plexus, respectively. In the absence of good clinical predictors, preoperative urodynamic examinations could have a role in understanding the pathophysiology of the dysfunction before such interventions. The pathophysiology of lower urinary tract dysfunction following radical hysterectomy is multifactorial. Its management is complex and should be multidisciplinary. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  15. Lower Miocene echinoderms of Jamaica, West Indies

    NARCIS (Netherlands)

    Donovan, S.K.; Portell, R.W.; Veltkamp, C.J.

    2005-01-01

    Despite being diverse globally, Miocene echinoids are poorly known from Jamaica. Moderately diverse echinoids and other echinoderms have been identified mainly from fragmentary specimens collected from chalks and mass-flow deposits of the Lower Miocene Montpelier Formation, White Limestone Group,

  16. Lower limb asymmetry in mechanical muscle function

    DEFF Research Database (Denmark)

    Jordan, M J; Aagaard, Per; Herzog, W

    2015-01-01

    ) for kinetic impulse (CMJ and SJ phase-specific kinetic impulse AI). Dual x-ray absorptiometry scanning was used to assess asymmetry in lower body muscle mass. Compared with controls, ACL-R skiers had increased AI in muscle mass (P 

  17. Circuit lower bounds in bounded arithmetics

    Czech Academy of Sciences Publication Activity Database

    Pich, Ján

    2015-01-01

    Roč. 166, č. 1 (2015), s. 29-45 ISSN 0168-0072 R&D Projects: GA AV ČR IAA100190902 Keywords : bounded arithmetic * circuit lower bounds Subject RIV: BA - General Mathematics Impact factor: 0.582, year: 2015 http://www.sciencedirect.com/science/article/pii/S0168007214000888

  18. Lipid-lowering treatment to the end?

    DEFF Research Database (Denmark)

    Petersen, Line Kirkeby; Christensen, Kaare; Kragstrup, Jakob

    2010-01-01

    People aged 80 or older are the fastest growing population in high-income countries. One of the most common causes of death among the elderly is the cardiovascular disease (CVD). Lipid-lowering treatment is common, e.g. one-third of 75-84-year-old Swedes are treated with statins. The assumption...

  19. Exploring the Limits of Frequency Lowering

    Science.gov (United States)

    Souza, Pamela E.; Arehart, Kathryn H.; Kates, James M.; Croghan, Naomi B. H.; Gehani, Namita

    2013-01-01

    Purpose: This study examined how frequency lowering affected sentence intelligibility and quality for adults with postlingually acquired, mild-to-moderate hearing loss. Method: Listeners included adults aged 60-92 years with sloping sensorineural hearing loss and a control group of similarly aged adults with normal hearing. Sentences were…

  20. The last LHC dipole magnet is lowered

    CERN Multimedia

    Claudia Marcelloni

    2007-01-01

    A ceremony is held as the last of 1746 superconducting magnets is lowered into the 27-km circumference tunnel that houses the LHC. The LHC project leader, Lyn Evans, changes a banner reading ‘first magnet for the LHC’ to ‘last magnet for the LHC’ in his native Welsh.

  1. Generalized Lower and Upper Approximations in Quantales

    Directory of Open Access Journals (Sweden)

    Qimei Xiao

    2012-01-01

    Full Text Available We introduce the concepts of set-valued homomorphism and strong set-valued homomorphism of a quantale which are the extended notions of congruence and complete congruence, respectively. The properties of generalized lower and upper approximations, constructed by a set-valued mapping, are discussed.

  2. Transperitoneal laparoscopic ureteric reimplantation for lower ...

    African Journals Online (AJOL)

    V. Singh

    2016-07-21

    Jul 21, 2016 ... Buttressing by detrusor muscle was done for cre- ation of anti-reflux mechanism by taking 3–4 interrupted sutures for. Table 1. Indications for laparoscopic ureteric reimplanation. Lower ureteric stricture. Ureterovaginal fistula. Pelvic surgeries (like hystrectomy and pelvic mass excision). Ureterolithotomy.

  3. Running With an Elastic Lower Limb Exoskeleton.

    Science.gov (United States)

    Cherry, Michael S; Kota, Sridhar; Young, Aaron; Ferris, Daniel P

    2016-06-01

    Although there have been many lower limb robotic exoskeletons that have been tested for human walking, few devices have been tested for assisting running. It is possible that a pseudo-passive elastic exoskeleton could benefit human running without the addition of electrical motors due to the spring-like behavior of the human leg. We developed an elastic lower limb exoskeleton that added stiffness in parallel with the entire lower limb. Six healthy, young subjects ran on a treadmill at 2.3 m/s with and without the exoskeleton. Although the exoskeleton was designed to provide ~50% of normal leg stiffness during running, it only provided 24% of leg stiffness during testing. The difference in added leg stiffness was primarily due to soft tissue compression and harness compliance decreasing exoskeleton displacement during stance. As a result, the exoskeleton only supported about 7% of the peak vertical ground reaction force. There was a significant increase in metabolic cost when running with the exoskeleton compared with running without the exoskeleton (ANOVA, P exoskeletons for human running are human-machine interface compliance and the extra lower limb inertia from the exoskeleton.

  4. Explaining lower educated workers' training intentions

    NARCIS (Netherlands)

    Sanders, J.; Oomens, S.; Blonk, R.W.B.; Hazelzet, A.

    2011-01-01

    Purpose: The purpose of this study is to contribute to the discussion on how to increase lower educated workers' participation in training programs inside and outside the workplace through stimulating intentions with respect to training. Design/methodology/approach: This article is based on data

  5. Babesiosis in Lower Hudson Valley, New York

    Centers for Disease Control (CDC) Podcasts

    2011-05-12

    This podcast discusses a study about an increase in babesiosis in the Lower Hudson Valley of New York state. Dr. Julie Joseph, Assistant Professor of Medicine at New York Medical College, shares details of this study.  Created: 5/12/2011 by National Center for Emerging Zoonotic and Infectious Diseases (NCEZID).   Date Released: 5/23/2011.

  6. Return to work after lower limb amputation.

    Science.gov (United States)

    Burger, Helena; Marincek, Crt

    2007-09-15

    To review the literature on return to work after lower limb amputation. A comprehensive review of literature on return to work after lower limb amputation was carried out, searching MEDLINE and PubMED. Most authors found return-to-work rate to be about 66%. Between 22 and 67% of the subjects retained the same occupation, while the remainder had to change occupation. Post-amputation jobs were generally more complex with a requirement for a higher level of general educational development and were physically less demanding. The return to work depends on: general factors, such as age, gender and educational level; factors related to impairments and disabilities due to amputation (amputation level, multiple amputations, comorbidity, reason for amputation, persistent stump problems, the time from the injury to obtaining a permanent prosthesis, wearing comfort of the prosthesis, walking distance and restrictions in mobility); and factors related to work and policies (salary, higher job involvement, good support from the implementing body and the employer and social support network). Subjects have problems returning to work after lower limb amputation. Many have to change their work and/or work only part-time. Vocational rehabilitation and counselling should become a part of rehabilitation programme for all subjects who are of working age after lower limb amputation. Better cooperation between professionals, such as rehabilitation team members, implementing bodies, company doctors and the employers, is necessary.

  7. Glucose and triglyceride lowering activity of Pterocarpus ...

    African Journals Online (AJOL)

    Jane

    2010-08-02

    Aug 2, 2010 ... P. santalinoides possess triglyceride and glucose lowering properties in dexamethasone induced hyperlipidemia and insulin resistance and could be of therapeutic value in the management of metabolic syndrome. Key words: Pterocarpus santalinoides, leaf extracts, glucose tolerance, hyperlipidemia, ...

  8. Glucose and triglyceride lowering activity of Pterocarpus ...

    African Journals Online (AJOL)

    The leaf extracts of P. santalinoides possess triglyceride and glucose lowering properties in dexamethasone induced hyperlipidemia and insulin resistance and could be of therapeutic value in the management of metabolic syndrome. Key words: Pterocarpus santalinoides, leaf extracts, glucose tolerance, hyperlipidemia, ...

  9. The radiation analyses of ITER lower ports

    International Nuclear Information System (INIS)

    Petrizzi, L.; Brolatti, G.; Martin, A.; Loughlin, M.; Moro, F.; Villari, R.

    2010-01-01

    The ITER Vacuum Vessel has upper, equatorial, and lower ports used for equipment installation, diagnostics, heating and current drive systems, cryo-vacuum pumping, and access inside the vessel for maintenance. At the level of the divertor, the nine lower ports for remote handling, cryo-vacuum pumping and diagnostic are inclined downwards and toroidally located each every 40 o . The cryopump port has additionally a branch to allocate a second cryopump. The ports, as openings in the Vacuum Vessel, permit radiation streaming out of the vessel which affects the heating in the components in the outer regions of the machine inside and outside the ports. Safety concerns are also raised with respect to the dose after shutdown at the cryostat behind the ports: in such zones the radiation dose level must be kept below the regulatory limit to allow personnel access for maintenance purposes. Neutronic analyses have been required to qualify the ITER project related to the lower ports. A 3-D model was used to take into account full details of the ports and the lower machine surroundings. MCNP version 5 1.40 has been used with the FENDL 2.1 nuclear data library. The ITER 40 o model distributed by the ITER Organization was developed in the lower part to include the relevant details. The results of a first analysis, focused on cryopump system only, were recently published. In this paper more complete data on the cryopump port and analysis for the remote handling port and the diagnostic rack are presented; the results of both analyses give a complete map of the radiation loads in the outer divertor ports. Nuclear heating, dpa, tritium production, and dose rates after shutdown are provided and the implications for the design are discussed.

  10. The Lower Depths on the German Stage

    Directory of Open Access Journals (Sweden)

    Svetlana M. Demkina

    2018-03-01

    Full Text Available This article examines the stage history of M. Gorky’s play The Lower Depths in Germany. The author discusses German stage history of Gorky’s work against the social background and in the context of major artistic tendencies of the 20 th century. Steady interest in Gorky as a playwright in Germany is due to the acute social importance and universality of the problems reflected in his dramas. Bearing on the archive materials of the Gorky Museum, the essay explores interpretations of Gorky’s cult drama The Lower Depths in the work of European stage directors, acclaimed reformers of theatrical art. A significant part of the “Gorky and German Theater” section of the Gorky Museum (IWL RAS is devoted to The Lower Depths. Two series of photographs represent the first German staging of Nachtasyl (German translation of The Lower Depths. The performance of Max Reinhardt and Richard Vallentin in Berlin Kleines Theater on January 10–23, 1903, had great success and good takings. After the premiere, attention to the personality of Gorky in Europe increased; he became the most popular Sovietauthor. When Nazi came to power, they banned Gorky’s work in Germany: he reappeared on the German stage only after the World War II. In the late 1960s, on the wave of Gorky’s centenary (1968, world theatres ran a series of performances based on his plays. The 1970s were marked by a renewal of interest to Gorky the playwright. The Lower Depths was staged in Europe, the USA, and the UK. Both directors and critics perceived Gorky’s dramaturgy in the context of works of his contemporaries — Shaw, Ibsen, Hauptmann, Tolstoy, Chekhov.

  11. The relationship between lower limb muscle strength and lower extremity function in HIV disease

    Directory of Open Access Journals (Sweden)

    Peter C. Mhariwa

    2017-02-01

    Full Text Available Background: Human immunodeficiency virus (HIV negatively impacts muscle strength and function. This study aimed to establish the relationship between lower limb muscle strength and lower extremity function in HIV disease.Method: A cross-sectional study was undertaken with a sample of 113 HIV-positive participants. Lower limb muscle strength and self-reported function were established using dynamometry and the Lower Extremity Functional Scale (LEFS, respectively. Muscle strength and functional status were established in a subset of 30 HIV-negative participants to determine normative values.Results: Muscle strength for participants with HIV ranged from an ankle dorsiflexion mean of 9.33 kg/m2 to 15.79 kg/m2 in hip extensors. In the HIV-negative group, ankle dorsiflexors recorded 11.17 kg/m2, whereas hip extensors were the strongest, generating 17.68 kg/m2. In the HIV-positive group, linear regression showed a positive relationship between lower limb muscle strength and lower extremity function (r = 0.71, p = 0.00. Fifty per cent of the changes in lower extremity function were attributable to lower limb muscle strength. A simple linear regression model showed that lower limb ankle plantar flexors contributed the most to lower extremity function in this cohort, contrary to the literature which states that hip and trunk muscles are the most active in lower limb functional activities.Conclusion: Lower extremity strength impacts perceived function in individuals stabilised on antiretroviral therapy for HIV disease. These findings demonstrate that ankle plantar flexors produce more force over hip flexors. Careful attention should be paid to the implications for strength training in this population.

  12. Synthèse de peptidomimétiques contenant un scaffold dicetopiperazinique bifonctionnel et leur evaluation comme modulateurs de l'agrégation des peptides amyloides beta

    OpenAIRE

    Vahdati, Leïla

    2015-01-01

    The formation of peptide and protein aggregates through the interaction of β-sheets has increasingly drawn attention since it occurs in many widespread human diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson's disease (PD), prion diseases, and Huntington's disease (HD). Alzheimer’s disease is the most common form of dementia that causes memory loss in the elderly. In 2013, 35 million people were afflicted with AD worldwide, a number expected to double ...

  13. 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

    Science.gov (United States)

    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

    2012-01-01

    In vivo imaging and quantification of amyloid-β plaque (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 with [11C]PiB and specific activities commonly used in human studies. In vivo mouse brain MRI for anatomical reference was acquired with a clinical 1.5 T system. A recently characterized APP/PS1 mouse was employed to measure Aβ at different disease stages in homozygous and hemizygous animals. We performed multi-modal cross-validations for the PET results with ex vivo and in vitro methodologies, including regional brain biodistribution, multi-label digital autoradiography, protein quantification with ELISA, fluorescence microscopy, semi-automated histological quantification and radioligand binding assays. Specific [11C]PiB uptake in individual brain regions with Aβ deposition was demonstrated and validated in all animals of the study cohort including homozygous AD animals as young as nine months. Corresponding to the extent of Aβ pathology, old homozygous AD animals (21 months) showed the highest uptake followed by old hemizygous (23 months) and young homozygous mice (9 months). In all AD age groups the cerebellum was shown to be suitable as an intracerebral reference region. PET results were cross-validated and consistent with all applied ex vivo and in vitro methodologies. The results confirm that the experimental setup for non-invasive [11C]PiB imaging of Aβ in the APP/PS1 mice provides a feasible, reproducible and robust protocol for small-animal Aβ imaging. It allows longitudinal imaging studies with follow-up periods of approximately one and a half years and provides a foundation for translational Alzheimer neuroimaging in transgenic mice. PMID:22427802

  14. [WHICH IN SURGERY OF LOWER LIMB AMPUTATION].

    Science.gov (United States)

    Mezzetti, Roberto

    2015-01-01

    Lower limb amputation is in effect decisive surgery in the treatment of ischemic gangrene whether nature of post-traumatic or secondary to arterial disease of the lower limbs. The amputation is not however to be considered debulking surgery. The demolition regards the limb behind which we do not have the presence scotomize amputee who requires to be accompanied in dealing with a new life that has as its main objective the autonomy scope family and society. The search for a good level of amputation surgery then makes reconstructive surgery. The level of amputation will allow in fact the use ofprincipals able to guarantee the total autonomy. After an analysis of surgical techniques the author will then analyze the latest devices available in the permit to pursue the best possible level of amputation even in cases where the disease is starting to discourage the doctor.

  15. Lower head integrity under steam explosion loads

    Energy Technology Data Exchange (ETDEWEB)

    Theofanous, T.G.; Yuen, W.W.; Angelini, S.; Freeman, K.; Chen, X.; Salmassi, T. [Center for Risk Studies and Safety, Univ. of California, Santa Barbara, CA (United States); Sienicki, J.J.

    1998-01-01

    Lower head integrity under steam explosion loads in an AP600-like reactor design is considered. The assessment is the second part of an evaluation of the in-vessel retention idea as a severe accident management concept, the first part (DOE/ID-10460) dealing with thermal loads. The assessment is conducted in terms of the Risk Oriented Accident Analysis Methodology (ROAAM), and includes the comprehensive evaluation of all relevant severe accident scenarios, melt conditions and timing of release from the core region, fully 3D mixing and explosion wave dynamics, and lower head fragility under local, dynamic loading. All of these factors and brought together in a ROAAM Probabilistic Framework to evaluate failure likelihood. The conclusion is that failure is `physically unreasonable`. (author)

  16. Lower pinch radius limit in EXTRAP

    International Nuclear Information System (INIS)

    Lehnert, B.

    1989-01-01

    In an Extrap pinch there is a superimposed magnetic octupole field which forms a magnetic separatrix with the field generated by the pinch current. Earlier experiments have shown that the octupole field has a stabilizing influence on the plasma. Regardless of the details of this stabilizing mechanism, it is expected that the influence of the octupole field should become negligible for a sufficiently small ratio between the characteristic pinch and separatrix radii. In other words, there should exist a lower limit of this ratio below which the system approaches the state of an ordinary unstabilized Z-pinch. The present paper presents an extended version of an earlier theoretical model of this lower limit, and its relation to the corresponding critical ratio between the external conductor and pinch currents. This ratio is found to vary substantially with the plasma parameters. (authors)

  17. Lymphatic filariasis in Lower Shire, southern Malawi

    DEFF Research Database (Denmark)

    Nielsen, N. O.; Makaula, P.; Nyakuipa, D.

    2002-01-01

    Surveys for lymphatic filariasis were carried out for the first time in Lower Shire (Nsanje and Chikwawa Districts) of southern Malawi, in April-June 2000. There were 3 phases. In phase I, questionnaire surveys in 48 randomly selected villages indicated that chronic manifestations of lymphatic....... This was probably related to a recent increase in transmission of filariasis as a result of extensive flooding in the area prior to the study. The study indicated that lymphatic filariasis is highly endemic in the Lower Shire area of Malawi, and calls for action towards its control....... filariasis ('swollen scrotum' and 'swollen legs') were common and widespread in the area. In phase II, volunteers from 10 of the villages reporting frequent manifestations of filariasis in phase I were examined with the ICT whole-blood test for Wuchereria bancrofti-specific circulating filarial antigen (CFA...

  18. Floods and droughts on the lower Vistula

    Directory of Open Access Journals (Sweden)

    Marzenna Sztobryn

    2013-06-01

    Full Text Available The study analyses floods and droughts on the lower Vistula based on the data (water levels and flow rates recorded in stations of the Institute of Meteorology and Water Management – National Research Institute (IMGW-PIB in Warsaw, Kępa Polska, Toruń and Tczew. It also includes the causes of flooding and drought in the lower Vistula with the hydrological characteristics from the years 1951–2010. The variability in maximum and minimum annual and monthly flow rates has been analysed for the aforementioned period as well. In addition, the authors have analysed changes in the shape of the flood wave after passing through the reservoir and cascade in Włocławek based on the hydrograph of May and June 2010. It has been found that the flood wave is flattened and extended. This phenomenon is favourable from the point of view of flood actions.

  19. Lower limb vascular dysfunction in cyclists

    Directory of Open Access Journals (Sweden)

    Thiago Ayala Melo Di Alencar

    2013-06-01

    Full Text Available Sports-related vascular insufficiency affecting the lower limbs is uncommon, and early signs and symptoms can be confused with musculoskeletal injuries. This is also the case among professional cyclists, who are always at the threshold between endurance and excess training. The aim of this review was to analyze the occurrence of vascular disorders in the lower limbs of cyclists and to discuss possible etiologies. Eighty-five texts, including papers and books, published from 1950 to 2012, were used. According to the literature reviewed, some cyclists receive a late diagnosis of vascular dysfunction due to a lack of familiarity of the medical team with this type of dysfunction. Data revealed that a reduced blood flow in the external iliac artery, especially on the left, is much more common than in the femoral and popliteal arteries, and that vascular impairment is responsible for the occurrence of early fatigue and reduced performance in cycling.

  20. Chlamydia and Male Lower Urinary Tract Diseases

    OpenAIRE

    Lee, Young-Suk; Lee, Kyu-Sung

    2013-01-01

    Of the chlamydia species that can cause infections in humans, C. trachomatis is responsible for lower urinary tract diseases in men and women. C. trachomatis infections are prevalent worldwide, but current research is focused on females, with the burden of disease and infertility sequelae considered to be a predominantly female problem. However, a role for this pathogen in the development of male urethritis, epididymitis, and orchitis is widely accepted. Also, it can cause complications such ...

  1. Cold stress induces lower urinary tract symptoms.

    Science.gov (United States)

    Imamura, Tetsuya; Ishizuka, Osamu; Nishizawa, Osamu

    2013-07-01

    Cold stress as a result of whole-body cooling at low environmental temperatures exacerbates lower urinary tract symptoms, such as urinary urgency, nocturia and residual urine. We established a model system using healthy conscious rats to explore the mechanisms of cold stress-induced detrusor overactivity. In this review, we summarize the basic findings shown by this model. Rats that were quickly transferred from room temperature (27 ± 2°C) to low temperature (4 ± 2°C) showed detrusor overactivity including increased basal pressure and decreased voiding interval, micturition volume, and bladder capacity. The cold stress-induced detrusor overactivity is mediated through a resiniferatoxin-sensitve C-fiber sensory nerve pathway involving α1-adrenergic receptors. Transient receptor potential melastatin 8 channels, which are sensitive to thermal changes below 25-28°C, also play an important role in mediating the cold stress responses. Additionally, the sympathetic nervous system is associated with transient hypertension and decreases of skin surface temperature that are closely correlated with the detrusor overactivity. With this cold stress model, we showed that α1-adrenergic receptor antagonists have the potential to treat cold stress-exacerbated lower urinary tract symptoms. In addition, we showed that traditional Japanese herbal mixtures composed of Hachimijiogan act, in part, by increasing skin temperature and reducing the number of cold sensitive transient receptor potential melastatin channels in the skin. The effects of herbal mixtures have the potential to treat and/or prevent the exacerbation of lower urinary tract symptoms by providing resistance to the cold stress responses. Our model provides new opportunities for utilizing animal disease models with altered lower urinary tract functions to explore the effects of novel therapeutic drugs. © 2013 The Japanese Urological Association.

  2. Neuropeptides in Lower Urinary Tract (LUT) Function

    OpenAIRE

    Arms, Lauren; Vizzard, Margaret A.

    2011-01-01

    Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and non-neural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bla...

  3. Hydroxychloroquine as a glucose lowering drug

    OpenAIRE

    Winter, Elizabeth Martha; Schrander-van der Meer, Anita; Eustatia-Rutten, Carmen; Janssen, Martien

    2011-01-01

    The authors report a remarkable glucose lowering side effect of the often used drug hydroxychloroquine (Plaquenil) in an otherwise healthy non-diabetic patient, who presented with severe hypoglycaemia. Although the mechanism has not been clarified yet, increased insulin sensitivity as well as decreased insulin degradation is suggested to contribute to the reduction in serum glucose levels. Clinicians prescribing this drug must be warranted and check glucose levels in the initial phase. Moreov...

  4. EXPLICIT LOWER BOUNDS FOR LINEAR FORMS

    DEFF Research Database (Denmark)

    Leppälä, Kalle

    2016-01-01

    Let I be the field of rational numbers or an imaginary quadratic field and Z(I) its ring of integers. We study some general lemmas that produce lower bounds vertical bar B-0 + B-1 theta(1) +... + B-r theta(r)vertical bar >= 1/max{vertical bar B-1 vertical bar,...,vertical bar B-r vertical bar}(mu...

  5. The central part of CMS is lowered

    CERN Multimedia

    Maximilien Brice

    2007-01-01

    On 28 February 2007, the CMS central piece containing the magnet and weighing as much as five Jumbo jets (1920 tonnes) was gently lowered into place. Only 20 cm separated the detector, which was suspended by four huge cables, each with 55 strands and sophisticated monitoring to minimize sway and tilt, from the walls of the shaft. The entire process took about 10 hours to complete.

  6. Lower limb loading in step aerobic dance.

    Science.gov (United States)

    Wu, H-W; Hsieh, H-M; Chang, Y-W; Wang, L-H

    2012-11-01

    Participation in aerobic dance is associated with a number of lower extremity injuries, and abnormal joint loading seems to be a factor in these. However, information on joint loading is limited. The purpose of this study was to investigate the kinetics of the lower extremity in step aerobic dance and to compare the differences of high-impact and low-impact step aerobic dance in 4 aerobic movements (mambo, kick, L step and leg curl). 18 subjects were recruited for this study. High-impact aerobic dance requires a significantly greater range of motion, joint force and joint moment than low-impact step aerobic dance. The peak joint forces and moments in high-impact step aerobic dance were found to be 1.4 times higher than in low-impact step aerobic dance. Understanding the nature of joint loading may help choreographers develop dance combinations that are less injury-prone. Furthermore, increased knowledge about joint loading may be helpful in lowering the risk of injuries in aerobic dance instructors and students. © Georg Thieme Verlag KG Stuttgart · New York.

  7. Lower urinary tract development and disease

    Science.gov (United States)

    Rasouly, Hila Milo; Lu, Weining

    2013-01-01

    Congenital Anomalies of the Lower Urinary Tract (CALUT) are a family of birth defects of the ureter, the bladder and the urethra. CALUT includes ureteral anomalies such as congenital abnormalities of the ureteropelvic junction (UPJ) and ureterovesical junction (UVJ), and birth defects of the bladder and the urethra such as bladder-exstrophy-epispadias complex (BEEC), prune belly syndrome (PBS), and posterior urethral valves (PUV). CALUT is one of the most common birth defects and is often associated with antenatal hydronephrosis, vesicoureteral reflux (VUR), urinary tract obstruction, urinary tract infections (UTI), chronic kidney disease and renal failure in children. Here, we discuss the current genetic and molecular knowledge about lower urinary tract development and genetic basis of CALUT in both human and mouse models. We provide an overview of the developmental processes leading to the formation of the ureter, bladder, and urethra, and different genes and signaling pathways controlling these developmental processes. Human genetic disorders that affect the ureter, bladder and urethra and associated gene mutations are also presented. As we are entering the post-genomic era of personalized medicine, information in this article may provide useful interpretation for the genetic and genomic test results collected from patients with lower urinary tract birth defects. With evidence-based interpretations, clinicians may provide more effective personalized therapies to patients and genetic counseling for their families. PMID:23408557

  8. Neural Control of the Lower Urinary Tract

    Science.gov (United States)

    de Groat, William C.; Griffiths, Derek; Yoshimura, Naoki

    2015-01-01

    This article summarizes anatomical, neurophysiological, pharmacological, and brain imaging studies in humans and animals that have provided insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract. The functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain, spinal cord, and peripheral autonomic ganglia that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet. The neural control of micturition is organized as a hierarchical system in which spinal storage mechanisms are in turn regulated by circuitry in the rostral brain stem that initiates reflex voiding. Input from the forebrain triggers voluntary voiding by modulating the brain stem circuitry. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic reflex pathway that has essential connections in the periaqueductal gray and pontine micturition center. A computer model of this circuit that mimics the switching functions of the bladder and urethra at the onset of micturition is described. Micturition occurs involuntarily in infants and young children until the age of 3 to 5 years, after which it is regulated voluntarily. Diseases or injuries of the nervous system in adults can cause the re-emergence of involuntary micturition, leading to urinary incontinence. Neuroplasticity underlying these developmental and pathological changes in voiding function is discussed. PMID:25589273

  9. [Lower extremity amputation rates in diabetic patients].

    Science.gov (United States)

    Cisneros-González, Nelly; Ascencio-Montiel, Iván Jesús; Libreros-Bango, Vita Norma; Rodríguez-Vázquez, Héctor; Campos-Hernández, Ángel; Dávila-Torres, Javier; Kumate-Rodríguez, Jesús; Borja-Aburto, Víctor Hugo

    2016-01-01

    The lower extremity amputations diminish the quality of life of patients with Diabetes Mellitus (DM). The aim of this study was to describe the lower extremity amputation rates in subjects with DM in the Mexican Social Security Institute (IMSS), comparing 2004 and 2013. A comparative cross-sectional study was done. Amputations were identified from the hospital records of System of Medical Statistics (DataMart). The DM patient census was obtained from the System of Integral Attention to Health. Major and minor amputations rates were expressed per 100,000 DM patients. We observed 2 334 340 and 3 416 643 DM patients during 2004 and 2013, respectively. The average age at the time of the amputation was similar in 2004 and 2013 (61.7 and 65.6 years old for minor and major amputations respectively). The major amputations rates were 100.9 and 111.1 per 100 000 subjects with DM in during 2004 and 2013 (p = 0.001); while minor amputations rates were 168.8 and 162.5 per 100 000 subjects with DM in during 2004 and 2013 respectively (p = 0.069). The lower extremity amputations rates at IMSS are very high compared with that reported in developed countries. The major amputations rate increased in 2013 compared with 2004.

  10. Accepting Lower Salaries for Meaningful Work

    Directory of Open Access Journals (Sweden)

    Jing Hu

    2017-09-01

    Full Text Available A growing literature indicates that people are increasingly motivated to experience a sense of meaning in their work lives. Little is known, however, about how perceptions of work meaningfulness influence job choice decisions. Although much of the research on job choice has focused on the importance of financial compensation, the subjective meanings attached to a job should also play a role. The current set of studies explored the hypothesis that people are willing to accept lower salaries for more meaningful work. In Study 1, participants reported lower minimum acceptable salaries when comparing jobs that they considered to be personally meaningful with those that they considered to be meaningless. In Study 2, an experimental enhancement of a job’s apparent meaningfulness lowered the minimum acceptable salary that participants required for the position. In two large-scale cross-national samples of full-time employees in 2005 and 2015, Study 3 found that participants who experienced more meaningful work lives were more likely to turn down higher-paying job offers elsewhere. The strength of this effect also increased significantly over this time period. Study 4 replicated these findings in an online sample, such that participants who reported having more meaningful work were less willing to leave their current jobs and organizations for higher paying opportunities. These patterns of results remained significant when controlling for demographic factors and differences in job characteristics.

  11. Accepting Lower Salaries for Meaningful Work.

    Science.gov (United States)

    Hu, Jing; Hirsh, Jacob B

    2017-01-01

    A growing literature indicates that people are increasingly motivated to experience a sense of meaning in their work lives. Little is known, however, about how perceptions of work meaningfulness influence job choice decisions. Although much of the research on job choice has focused on the importance of financial compensation, the subjective meanings attached to a job should also play a role. The current set of studies explored the hypothesis that people are willing to accept lower salaries for more meaningful work. In Study 1, participants reported lower minimum acceptable salaries when comparing jobs that they considered to be personally meaningful with those that they considered to be meaningless. In Study 2, an experimental enhancement of a job's apparent meaningfulness lowered the minimum acceptable salary that participants required for the position. In two large-scale cross-national samples of full-time employees in 2005 and 2015, Study 3 found that participants who experienced more meaningful work lives were more likely to turn down higher-paying job offers elsewhere. The strength of this effect also increased significantly over this time period. Study 4 replicated these findings in an online sample, such that participants who reported having more meaningful work were less willing to leave their current jobs and organizations for higher paying opportunities. These patterns of results remained significant when controlling for demographic factors and differences in job characteristics.

  12. Lower Extremity Permanent Dialysis Vascular Access.

    Science.gov (United States)

    Parekh, Vishal B; Niyyar, Vandana D; Vachharajani, Tushar J

    2016-09-07

    Hemodialysis remains the most commonly used RRT option around the world. Technological advances, superior access to care, and better quality of care have led to overall improvement in survival of patients on long-term hemodialysis. Maintaining a functioning upper extremity vascular access for a prolonged duration continues to remain a challenge for dialysis providers. Frequently encountered difficulties in clinical practice include (1) a high incidence of central venous catheter-related central vein stenosis and (2) limited options for creating a functioning upper extremity permanent arteriovenous access. Lack of surgical skills, fear of complications, and limited involvement of the treating nephrologists in the decision-making process are some of the reasons why lower extremity permanent dialysis access remains an infrequently used option. Similar to upper extremity vascular access options, lower extremity arteriovenous fistula remains a preferred access over arteriovenous synthetic graft. The use of femoral tunneled catheter as a long-term access should be avoided as far as possible, especially with the availability of newer graft-catheter hybrid devices. Our review provides a summary of clinical evidence published in surgical, radiology, and nephrology literature highlighting the pros and cons of different types of lower extremity permanent dialysis access. Copyright © 2016 by the American Society of Nephrology.

  13. Life after lower extremity amputation in diabetics.

    Science.gov (United States)

    Cox, P St L; Williams, S K P; Weaver, S R

    2011-10-01

    Lower limb amputees typically have reduced mobility which affects their ability to perform daily tasks and to successfully reintegrate into community life. A major goal of rehabilitation for amputees is to improve quality of life (QOL). This study therefore focussed on QOL and functional independence for persons with lower limb amputations secondary to diabetes. To determine the QOL and functional independence of lower limb diabetic amputees one to three years post amputation, using variables such as age, gender and amputation level. A total of 87 participants were selected from the 2006-2009 physiotherapy records at the St Ann's Bay Hospital. These participants completed the World Health Organization Quality of Life Scale (WHO QOL-BREF) and the Functional Independence Measure (FIM). Data were analysed using SPSS (version 12) and the mean values for QOL and functional independence were calculated. Relationships between the variables: age, gender and level of amputation with QOL and functional independence were analysed using descriptive and inferential statistical techniques. Among the 35 males and 52 females participating in the study, below knee amputees recorded higher scores for QOL (p quality of life of all participants. The results showed that below knee amputees functioned better than those with above knee amputations and that females were more likely to cope and function with the disability than males.

  14. Lower urinary tract development and disease.

    Science.gov (United States)

    Rasouly, Hila Milo; Lu, Weining

    2013-01-01

    Congenital anomalies of the lower urinary tract (CALUT) are a family of birth defects of the ureter, the bladder, and the urethra. CALUT includes ureteral anomaliesc such as congenital abnormalities of the ureteropelvic junction (UPJ) and ureterovesical junction (UVJ), and birth defects of the bladder and the urethra such as bladder-exstrophy-epispadias complex (BEEC), prune belly syndrome (PBS), and posterior urethral valves (PUVs). CALUT is one of the most common birth defects and is often associated with antenatal hydronephrosis, vesicoureteral reflux (VUR), urinary tract obstruction, urinary tract infections (UTI), chronic kidney disease, and renal failure in children. Here, we discuss the current genetic and molecular knowledge about lower urinary tract development and genetic basis of CALUT in both human and mouse models. We provide an overview of the developmental processes leading to the formation of the ureter, the bladder, and the urethra, and different genes and signaling pathways controlling these developmental processes. Human genetic disorders that affect the ureter, the bladder and the urethra and associated gene mutations are also presented. As we are entering the postgenomic era of personalized medicine, information in this article may provide useful interpretation for the genetic and genomic test results collected from patients with lower urinary tract birth defects. With evidence-based interpretations, clinicians may provide more effective personalized therapies to patients and genetic counseling for their families. Copyright © 2013 Wiley Periodicals, Inc.

  15. Effect of lower limb rehabilitation robot on lower limb motor function of hemiplegic patients after stroke

    Directory of Open Access Journals (Sweden)

    Jian-liang LU

    2017-07-01

    Full Text Available Objective To observe the rehabilitation effect of lower limb rehabilitation robot training on the lower limb motor function of hemiplegic patients after stroke. Methods A total of 60 stroke patients (duration < 6 months accepted conventional rehabilitation training combined with body weight support treadmill training (BWSTT group, N = 30 or conventional rehabilitation training combined with lower limb rehabilitation robot training (Robot group, N = 30. Fugl - Meyer Assessment Scale for Lower Extremity (FMA-LE was used to evaluate lower limb motor function. Berg Balance Scale (BBS was used to evaluate balance function. Lower limb rehabilitation robot torque feedback system was used to evaluate lower limb muscle strength. All evaluations were performed before and after 8-week training.   Results Compared with before training, the FMA-LE score (P = 0.000, BBS score (P = 0.000, hemiplegic side of hip joint feedback torque value (HJTV, P = 0.000 and knee joint feedback torque value (KJTV, P = 0.000 were increased in both groups after 8-week training. Compared with BWSTT group, the hemiplegic side of HJTV (P = 0.000 and KJTV (P = 0.000 were increased in Robot group after 8-week training, while the FMA-LE score (P = 0.118 and BBS score (P = 0.159 had no statistically significant difference between 2 groups.  Conclusions The lower limb rehabilitation robot or body weight support treadmill training combined with conventional rehabilitation training could improve the lower limb motor function of hemiplegic patients after stroke. The lower limb rehabilitation robot training was better than body weight support treadmill training on the recovery of lower limb muscle strength. DOI: 10.3969/j.issn.1672-6731.2017.05.004  

  16. Symbiotic fungal associations in 'lower' land plants.

    Science.gov (United States)

    Read, D J; Ducket, J G; Francis, R; Ligron, R; Russell, A

    2000-06-29

    An analysis of the current state of knowledge of symbiotic fungal associations in 'lower' plants is provided. Three fungal phyla, the Zygomycota, Ascomycota and Basidiomycota, are involved in forming these associations, each producing a distinctive suite of structural features in well-defined groups of 'lower' plants. Among the 'lower' plants only mosses and Equisetum appear to lack one or other of these types of association. The salient features of the symbioses produced by each fungal group are described and the relationships between these associations and those formed by the same or related fungi in 'higher' plants are discussed. Particular consideration is given to the question of the extent to which root fungus associations in 'lower' plants are analogous to 'mycorrhizas' of 'higher' plants and the need for analysis of the functional attributes of these symbioses is stressed. Zygomycetous fungi colonize a wide range of extant lower land plants (hornworts, many hepatics, lycopods, Ophioglossales, Psilotales and Gleicheniaceae), where they often produce structures analogous to those seen in the vesicular-arbuscular (VA) mycorrhizas of higher plants, which are formed by members of the order Glomales. A preponderance of associations of this kind is in accordance with palaeohbotanical and molecular evidence indicating that glomalean fungi produced the archetypal symbioses with the first plants to emerge on to land. It is shown, probably for the first time, that glomalean fungi forming typical VA mycorrhiza with a higher plant (Plantago lanceolata) can colonize a thalloid liverwort (Pellia epiphylla), producing arbuscules and vesicles in the hepatic. The extent to which these associations, which are structurally analogous to mycorrhizas, have similar functions remains to be evaluated. Ascomycetous associations are found in a relatively small number of families of leafy liverworts. The structural features of the fungal colonization of rhizoids and underground axes of

  17. MR imaging in congenital lower limb deformities

    International Nuclear Information System (INIS)

    Laor, T.; Jaramillo, D.; Hoffer, F.A.; Kasser, J.R.

    1996-01-01

    Treatment for children with cogenital deformities of the lower extremities may vary, depending on the state of the unossified skeletal structures and surrounding soft tissues. The purpose of our study was to demonstrate the spectrum of the osteochondral and extrasosseous abnormalities as depicted with MR imaging. We retrospectively reviewed MR examinations of 13 limbs of ten children (aged 1 month-9 years, mean 2.1 years) with longitudinal and transverse deformities of the lower extremities. The lesions imaged were fibular hemimelia (n=5), tibial hemimelia (n=5), and congenital constriction bands (n=3). Each examination was assessed for abnormalities in the osteocartilaginous and extraosseous (articular or periarticular components such as ligaments, tendons, and menisci; the muscles and the arteries) structures. Abnormalities were seen in all patients. Osteocartilaginous abnormalities in the patients with longitudinal deformities included abnormal distal femoral epiphyses, abnormal proximal tribial physes, hypertrophied and dislocated proximal fibular epiphyses, unsuspected fibular and tibial remnants, and absence or coalition of the tarsal bones. No osteocartilaginous abnormalities were seen in the patients with congential constriction bands. Articular abormalities in patients with either form of hemimelia included absent cruciate ligaments and menisci, dislocated or absent cartilaginous patellae, absent patellar tendons, and abnormal collateral ligaments. All but one limb imaged had absent or attenuated muscle groups. Of the nine MR arteriograms performed at the level of the knee, eight were abnormal. The normal popliteal trifurcation was absent or in an abnormal location. We conclude that MR imaging of children with congenital lower extremity deformities shows many osteochondral and extraosseous abnormalities that are not depicted by conventional radiogrpahy. This information can help to plan early surgical intervention and prosthetic rehabilitation. (orig.)

  18. MR imaging in congenital lower limb deformities

    Energy Technology Data Exchange (ETDEWEB)

    Laor, T. [Dept. of Radiology, Children`s Hospital and Harvard Medical School, Boston, MA (United States); Jaramillo, D. [Dept. of Radiology, Children`s Hospital and Harvard Medical School, Boston, MA (United States); Hoffer, F.A. [Dept. of Radiology, Children`s Hospital and Harvard Medical School, Boston, MA (United States); Kasser, J.R. [Dept. of Orthopedics, Children`s Hospital and Harvard Medical School, Boston, MA (United States)

    1996-06-01

    Treatment for children with cogenital deformities of the lower extremities may vary, depending on the state of the unossified skeletal structures and surrounding soft tissues. The purpose of our study was to demonstrate the spectrum of the osteochondral and extrasosseous abnormalities as depicted with MR imaging. We retrospectively reviewed MR examinations of 13 limbs of ten children (aged 1 month-9 years, mean 2.1 years) with longitudinal and transverse deformities of the lower extremities. The lesions imaged were fibular hemimelia (n=5), tibial hemimelia (n=5), and congenital constriction bands (n=3). Each examination was assessed for abnormalities in the osteocartilaginous and extraosseous (articular or periarticular components such as ligaments, tendons, and menisci; the muscles and the arteries) structures. Abnormalities were seen in all patients. Osteocartilaginous abnormalities in the patients with longitudinal deformities included abnormal distal femoral epiphyses, abnormal proximal tribial physes, hypertrophied and dislocated proximal fibular epiphyses, unsuspected fibular and tibial remnants, and absence or coalition of the tarsal bones. No osteocartilaginous abnormalities were seen in the patients with congential constriction bands. Articular abormalities in patients with either form of hemimelia included absent cruciate ligaments and menisci, dislocated or absent cartilaginous patellae, absent patellar tendons, and abnormal collateral ligaments. All but one limb imaged had absent or attenuated muscle groups. Of the nine MR arteriograms performed at the level of the knee, eight were abnormal. The normal popliteal trifurcation was absent or in an abnormal location. We conclude that MR imaging of children with congenital lower extremity deformities shows many osteochondral and extraosseous abnormalities that are not depicted by conventional radiogrpahy. This information can help to plan early surgical intervention and prosthetic rehabilitation. (orig.)

  19. Lower extremity amputation: a contemporary series.

    Science.gov (United States)

    Stone, Patrick A; Flaherty, Sarah K; Hayes, J David; AbuRahma, Ali F

    2007-01-01

    We sought to identify the results achieved with lower extremity amputations performed by both community and university-based surgeons as well as from multiple disciplines (orthopedic/general/vascular surgeons) serving a predominantly nonurban population. A review of 411 consecutive patients undergoing 508 non-traumatic lower extremity amputations at Charleston Area Medical Center from January 1999 to December 2003 was conducted. Amputations were performed most frequently at the below knee level (50.9%). Perioperative mortality (30-day) for the cohort was 11%. Mortality increased with more proximal level of initial amputations: 1.6% for transmetatarsal, 3.6% for below knee, 17.6% for above knee and 100% of those requiring hip disarticulation. Stump failure requiring conversion to a more proximal level was seen in 34.5% of TMA's, 12% of BKA, 6% of AKA during the follow-up period. Twenty-one percent of patients required bilateral amputations by the end of the follow-up period. Non-wound related morbidity for all procedures (i.e. pneumonia, stroke, renal failure) was 29%. Rehabilitation documentation was available for 55% of the cohort, of whom only 27% (N=61) were fitted for, and ambulating with a prosthesis during the follow-up period. Survival at 6 months, 1 year and 2 years was 59%, 47% and 23% respectively. Patients requiring major lower extremity amputation represent the peak of high-risk patients undergoing vascular surgery. Significant perioperative morbidity and limited survival is seen in this cohort. Early vascular surgery referral may reduce more proximal amputations and improve functional outcome in a group with poor longevity and limited functional capacity with amputation at the transtibial level and proximal.

  20. Cocaine-associated lower limb ischemia.

    LENUS (Irish Health Repository)

    Collins, Chris G

    2011-07-25

    Cocaine-associated thrombosis has been reported in the literature with reports of vascular injuries to cardiac, pulmonary, intestinal, placental, and musculoskeletal vessels; however, injury of the pedal vessels is rare. We report on a 31-year-old man who presented 2 months following a cocaine binge with limb-threatening ischemia without an otherwise identifiable embolic source. Angiography confirmed extensive occlusive disease of the tibioperoneal vessels. The patient improved following therapy with heparin and a prostacyclin analogue. Cocaine-induced thrombosis should be considered in patients presenting with acute arterial insufficiency in the lower limb without any other identifiable cause.

  1. Lower bound for the nuclear kinetic energy

    Energy Technology Data Exchange (ETDEWEB)

    Dehesa, J.S. (Granada Univ. (Spain). Dept. de Fisica Nuclear); Galvez, F.J. (Granada Univ. (Spain). Dept. de Fisica Teorica)

    1985-06-27

    We argue that the kinetic energy of a many-fermion system is bounded from below by Kqsup(-2/3)A sup(5/3) / , with K = 0.565 where q is the number of spin states available to each particle and sup(1/2) is the root mean square radius of the single-particle density. A simple lower bound for the nuclear kinetic energy is found. Numerical values of the bound for several nuclei are shown, and a comparison with some self-consistent calculations and some pseudo-empirical values is made.

  2. The Mather problem for lower semicontinuous Lagrangians

    KAUST Repository

    Gomes, Diogo A.

    2013-08-01

    In this paper we develop the Aubry-Mather theory for Lagrangians in which the potential energy can be discontinuous. Namely we assume that the Lagrangian is lower semicontinuous in the state variable, piecewise smooth with a (smooth) discontinuity surface, as well as coercive and convex in the velocity. We establish existence of Mather measures, various approximation results, partial regularity of viscosity solutions away from the singularity, invariance by the Euler-Lagrange flow away from the singular set, and further jump conditions that correspond to conservation of energy and tangential momentum across the discontinuity. © 2013 Springer Basel.

  3. The Mafic Lower Crust of Neoproterozoic age beneath Western Arabia: Implications for Understanding African Lower Crust

    Science.gov (United States)

    Stern, R. J.; Mooney, W. D.

    2011-12-01

    We review evidence that the lower crust of Arabia - and by implication, that beneath much of Africa was formed at the same time as the upper crust, rather than being a product of Cenozoic magmatic underplating. Arabia is a recent orphan of Africa, separated by opening of the Red Sea ~20 Ma, so our understanding of its lower crust provides insights into that of Africa. Arabian Shield (exposed in W. Arabia) is mostly Neoproterozoic (880-540 Ma) reflecting a 300-million year process of continental crustal growth due to amalgamated juvenile magmatic arcs welded together by granitoid intrusions that make up as much as 50% of the Shield's surface. Seismic refraction studies of SW Arabia (Mooney et al., 1985) reveal two layers, each ~20 km thick, separated by a well-defined Conrad discontinuity. The upper crust has average Vp ~6.3 km/sec whereas the lower crust has average Vp ~7.0 km/sec, corresponding to a granitic upper crust and gabbroic lower crust. Neogene (Yemen to Syria. Many of these lavas contain xenoliths, providing a remarkable glimpse of the lower-crustal and upper-mantle lithosphere beneath W. Arabia. Lower crustal xenoliths brought up in 8 harrats in Saudi Arabia, Jordan, and Syria are mostly 2-pyroxene granulites of igneous (gabbroic, anorthositic, and dioritic) origin. They contain plagioclase, orthopyroxene, and clinopyroxene, and a few contain garnet and rare amphibole and yield mineral-equilibrium temperatures of 700-900°C. Pyroxene-rich and plagioclase-rich suites have mean Al2O3 contents of 13% and 19%, respectively: otherwise the two groups have similar elemental compositions, with ~50% SiO2 and ~1% TiO2, with low K2O (time. Lower crust of Arabia clearly formed during Neoproterozoic time, about the same time as its upper crust complement; a similar origin for the lower crust beneath the broad expanses of Neoproterozoic crust in N and E Africa is likely. There is no evidence that any of the mafic lower crust of Arabia formed due to underplating by

  4. Nonallergic rhinitis and lower airway disease.

    Science.gov (United States)

    Rondón, C; Bogas, G; Barrionuevo, E; Blanca, M; Torres, M J; Campo, P

    2017-01-01

    In the past years, several investigators have demonstrated the existence of local nasal responses in some patients with typical allergic rhinitis symptoms but without atopy and have defined a new phenotype called local allergic rhinitis (LAR) or 'entopy'. In a percentage of LAR subjects, the upper airway disease is also associated with lower airway symptoms. After the description of this phenotype, the differential diagnosis between LAR and nonallergic rhinitis (NAR) has become a challenge for the clinician. To correctly identify LAR patients is of high importance for treatment and management of these patients, and for an appropriate inclusion of patients in clinical trials and genetics studies. The treatment of LAR patients, in contrast with NAR, is oriented to allergen avoidance and specific treatment. Allergen immunotherapy, the aetiological treatment for allergic respiratory diseases, has demonstrated to be an effective and safe treatment in LAR, increasing immunological tolerance, and reducing the clinical symptoms and the use of medication. In this article, the important and novel aspects of LAR in terms of mechanisms, diagnosis and treatment will be discussed. Also, the involvement of the lower airway and the potential role of IgE in the bronchial disease will be also reviewed. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. LOWER LIMB ASYMMETRIES IN RHYTHMIC GYMNASTICS ATHLETES.

    Science.gov (United States)

    Frutuoso, Anderson Simas; Diefenthaeler, Fernando; Vaz, Marco Aurélio; Freitas, Cintia de la Rocha

    2016-02-01

    Different limb training demands and limb preference may determine anthropometric and muscle force inter-limb asymmetries in Rhythmic Gymnastics (RG) athletes. The purpose of this study was to evaluate the influence of lateral preference of the lower extremity on anthropometric, range of motion, and isokinetic torque measurements of RG athletes. Cross sectional study. Lower limb anthropometric measurements (girth, estimated anatomical cross-sectional area), hip, knee and ankle range of motion, flexor and extensor isokinetic torques (angular velocities = 60, 180, e 240 °·s(-1)) and bilateral asymmetry index were evaluated in 11 international level Rhythmic Gymnastics athletes (17.9 ± 4.0 years of age; 9.1 ± 5,1 years of experience; 26.8 ± 6.0 weekly training hours). The preferred limb showed larger thigh girth and anatomical cross-sectional area, higher ankle dorsiflexor range of motion, higher hip flexor torque at 60 °·s(-1) and higher plantarflexor torque at 180 °·s(-1) compared to the non-preferred limb. The observed differences seem to be strictly related to lateral preference and rhythmic gymnastics training. 3.

  6. Determining lower threshold concentrations for synergistic effects

    DEFF Research Database (Denmark)

    Bjergager, Maj-Britt Andersen; Dalhoff, Kristoffer; Kretschmann, Andreas

    2017-01-01

    which proven synergists cease to act as synergists towards the aquatic crustacean Daphnia magna. To do this, we compared several approaches and test-setups to evaluate which approach gives the most conservative estimate for the lower threshold for synergy for three known azole synergists. We focus.......619±8.555μgL(-1)) and 0.122±0.0417μM (40.236±13.75μgL(-1)), respectively, in the 14-days tests. Testing synergy in relation to concentration addition provided the most conservative values. The threshold values for the vertical assessments in tests where the two could be compared were in general 1.2 to 4.......7 fold higher than the horizontal assessments. Using passive dosing rather than dilution series or spiking did not lower the threshold significantly. Below the threshold for synergy, slight antagony could often be observed. This is most likely due to induction of enzymes active in metabolization of alpha...

  7. Lower skin temperature decreases maximal cycling performance.

    Science.gov (United States)

    Imai, Daiki; Okazaki, Kazunobu; Matsumura, Shinya; Suzuki, Takashi; Miyazawa, Taiki; Suzuki, Akina; Takeda, Ryosuke; Hamamoto, Takeshi; Zako, Tetsuo; Kawabata, Takashi; Miyagawa, Toshiaki

    2011-12-01

    It is known that external cooling of body regions involved in exercise, prior to exercise, decreases anaerobic performance. However, there have been no studies reporting the effects of whole body skin surface cooling before exercise on maximal anaerobic capacity. In order to clarify the effects, we compared power output during the Wingate anaerobic test between preconditioning by exposure to temperature 10 degrees C and 25 degrees C. Eight healthy males carried out the Wingate test for 30 seconds, after pre-conditioning for 60 minutes using a perfusion suit with water at a temperature of 10 degrees C or 25 degrees C. We evaluated the peak power (PP) and peak power slope (PS) of the power output. Mean skin temperature (T(sk)) at 60 minutes of pre-conditioning in the 10 degrees C trial was significantly lower than in the 25 degrees C trial (p < 0.05). PP and also PS were significantly lower in the 10 degrees C trial than in the 25 degrees C trial. Changes (Δ) in PP between the 10 degrees C trial and the 25 degrees C trial were strongly correlated with ΔT(sk) and Δ in thigh and leg skin temperature (ΔT(thigh) and ΔT(leg), respectively), whereas ΔPS was strongly correlated with ΔT(sk), but not with ΔT(thigh) and ΔT(leg). Whole body skin surface cooling prior to exercise restricts anaerobic capacity, especially in the initial phase of exercise.

  8. Diagnosis of Lower Hybrid on MST

    International Nuclear Information System (INIS)

    Burke, D. R.; Goetz, J. A.; Kaufman, M. C.; Almagri, A. F.; Anderson, J. K.; Forest, C. B.; Prager, S. C.

    2007-01-01

    RF driven current has never been demonstrated in a Reversed Field Pinch. Recently the lower hybrid system on the Madison Symmetric Torus reached a new operating regime. This upgrade allows RF powers of up to 5% of the Ohmic input power to be injected. It is therefore anticipated that the lower hybrid system is on the threshold of producing meaningful changes to the RFP equilibrium. A diagnostic set is under development to facilitate the study of such changes and lay the foundation for near megawatt operations. Many measurements are being studied for viability. These include electron cyclotron emission, examinations of bulk ion and electron heating, surface perturbation pickup coils, magnetic probe measurements, and Langmuir probe measurements. In addition, several x-ray diagnostics are in operation: pulse height analysis is performed on detector arrays to determine the 5-200 keV spectrum. An insertable target probe is available to create x-rays from fast electrons. Tomographic inversion of 2-D Soft x-ray detectors yields equilibrium information through island structure. Results from experiments with source power up to 225 kW will be presented. Preliminary results from CQL3D Fokker-Planck simulations will also be presented

  9. Lipid Lowering with Soluble Dietary Fiber.

    Science.gov (United States)

    Surampudi, Prasanth; Enkhmaa, Byambaa; Anuurad, Erdembileg; Berglund, Lars

    2016-12-01

    Consumption of dietary soluble fibers has been associated with health benefits such as reduced lipid levels, lower blood pressure, improved blood glucose control, weight loss, improved immune function, and reduced inflammation. Many of these health benefits relate to a reduced risk of developing cardiovascular disease. In this paper, we have reviewed recent studies on the hypocholesterolemic effects of dietary soluble fibers as well as fiber-rich foods. Findings include the following: (a) consumption of water-soluble, viscous-forming fibers can reduce total and low-density lipoprotein cholesterol levels by about 5-10 %; (b) minimal changes of high-density lipoprotein cholesterol or triglyceride levels were observed; (c) cholesterol-lowering properties of soluble fibers depend on their physical and chemical properties; and (d) medium to high molecular weight fibers are more effective in reducing lipid levels. Hypocholesterolemic benefits were also observed with some fiber-rich foods, such as whole oats, whole barley, legumes, peas, beans, flax seeds, apples, and citrus foods.

  10. Arterial Stiffness in Lower Limb Amputees

    Directory of Open Access Journals (Sweden)

    Pedro Magalhães

    2011-01-01

    Full Text Available Background A high carotid-femoral pulse wave velocity (PWV has been related to increased cardiovascular morbidity and mortality, but has not been previously evaluated in amputees. The aim of this study was to compare PWV between amputees and nonamputees. Methods In this cross-sectional study, data were collected from 60 male lower limb amputees and 86 male age-matched nonamputees. PWV was measured noninvasively using a Complior ® device. All participants underwent laboratory investigations and anthropometry. The difference in PWV between amputee and nonamputees was estimated. Multivariate regression was used to adjust for differences between the groups as a result of potential confounders. Results PWV was higher in amputees than in nonamputees (10.8 ± 1.9 m/sec versus 9.9 ± 1.8 m/sec, P = 0.008, respectively. This difference remained even after adjusting for confounding factors. Conclusion A higher PWV was demonstrated in lower limb amputees. Routine assessment of PWV may contribute to cardiovascular risk stratification in amputees.

  11. Arterial Stiffness in Lower Limb Amputees

    Science.gov (United States)

    Magalhães, Pedro; Capingana, Daniel P.; Silva, Amílcar B.T.; Capunge, Inês R.; Gonçalves, Mauer A.A.

    2011-01-01

    Background: A high carotid-femoral pulse wave velocity (PWV) has been related to increased cardiovascular morbidity and mortality, but has not been previously evaluated in amputees. The aim of this study was to compare PWV between amputees and nonamputees. Methods: In this cross-sectional study, data were collected from 60 male lower limb amputees and 86 male age-matched nonamputees. PWV was measured noninvasively using a Complior® device. All participants underwent laboratory investigations and anthropometry. The difference in PWV between amputee and nonamputees was estimated. Multivariate regression was used to adjust for differences between the groups as a result of potential confounders. Results: PWV was higher in amputees than in nonamputees (10.8 ± 1.9 m/sec versus 9.9 ± 1.8 m/sec, P = 0.008, respectively). This difference remained even after adjusting for confounding factors. Conclusion: A higher PWV was demonstrated in lower limb amputees. Routine assessment of PWV may contribute to cardiovascular risk stratification in amputees. PMID:22084616

  12. Ambient air quality in Lower Town Quebec

    International Nuclear Information System (INIS)

    Sebez, S.

    2007-01-01

    A municipal waste incinerator near Lower Town Quebec has been identified as a major source of air pollution, notably emissions of dioxins, furans, nitrogen oxides (NOx), volatile organic matter (VOC) and polycyclic aromatic hydrocarbons (PAH). Combustion fumes contain gases such as carbon monoxide (CO), carbon dioxide (CO 2 ) and sulphur dioxide (SO 2 ), as well as dusts, fly ash and particulate matter that is easily airborne. The risks associated with poor air quality have been evaluated along with the effects of pollutants on young children, pregnant women, senior citizens and those with cardiac problems. Some studies have reported that exposure to NOx may cause lung cancer and certain VOCs can irritate the respiratory tract system. Air quality tests have also revealed the presence of mercury. In combination, all these pollutants create smog. The concrete actions that have been taken to address smog issues were discussed. The distance between the incinerator and different residential areas within Lower Town Quebec have been measured along with air quality. Health risks were found to be higher in areas closer to the incinerator. Major modifications have been recommended in order to reduce pollution emissions from the incinerator. These include modernizing the equipment, installing proper scrubbers, and to ultimately the close the incinerator if it continues to underperform. refs., tabs., figs

  13. Do lower vertebrates suffer from motion sickness?

    Science.gov (United States)

    Lychakov, Dmitri

    The poster presents literature data and results of the author’s studies with the goal to find out whether the lower animals are susceptible to motion sickness (Lychakov, 2012). In our studies, fish and amphibians were tested for 2 h and more by using a rotating device (f = 0.24 Hz, a _{centrifugal} = 0.144 g) and a parallel swing (f = 0.2 Hz, a _{horizontal} = 0.059 g). The performed studies did not revealed in 4 fish species and in toads any characteristic reactions of the motion sickness (sopite syndrome, prodromal preparatory behavior, vomiting). At the same time, in toads there appeared characteristic stress reactions (escape response, an increase of the number of urinations, inhibition of appetite), as well as some other reactions not associated with motion sickness (regular head movements, eye retractions). In trout fry the used stimulation promoted division of the individuals into the groups differing by locomotor reaction to stress, as well as the individuals with the well-expressed compensatory reaction that we called the otolithotropic reaction. Analysis of results obtained by other authors confirms our conclusions. Thus, the lower vertebrates, unlike mammals, are immune to motion sickness either under the land conditions or under conditions of weightlessness. On the basis of available experimental data and theoretical concepts of mechanisms of development the motion sickness, formulated in several hypotheses (mismatch hypothesis, Traisman‘ s hypothesis, resonance hypothesis), there presented the synthetic hypothesis of motion sickness that has the conceptual significance. According to the hypothesis, the unusual stimulation producing sensor-motor or sensor-sensor conflict or an action of vestibular and visual stimuli of frequency of about 0.2 Hz is perceived by CNS as poisoning and causes the corresponding reactions. The motion sickness actually is a byproduct of technical evolution. It is suggested that in the lower vertebrates, unlike mammals

  14. Environmental analysis of Lower Pueblo/Lower Los Alamos Canyon, Los Alamos, New Mexico

    International Nuclear Information System (INIS)

    Ferenbaugh, R.W.; Buhl, T.E.; Stoker, A.K.; Becker, N.M.; Rodgers, J.C.; Hansen, W.R.

    1994-12-01

    The radiological survey of the former radioactive waste treatment plant site (TA-45), Acid Canyon, Pueblo Canyon, and Los Alamos Canyon found residual contamination at the site itself and in the channel and banks of Acid, Pueblo, and lower Los Alamos Canyons all the way to the Rio Grande. The largest reservoir of residual radioactivity is in lower Pueblo Canyon, which is on DOE property. However, residual radioactivity does not exceed proposed cleanup criteria in either lower Pueblo or lower Los Alamos Canyons. The three alternatives proposed are (1) to take no action, (2) to construct a sediment trap in lower Pueblo Canyon to prevent further transport of residual radioactivity onto San Ildefonso Indian Pueblo land, and (3) to clean the residual radioactivity from the canyon system. Alternative 2, to cleanup the canyon system, is rejected as a viable alternative. Thousands of truckloads of sediment would have to be removed and disposed of, and this effort is unwarranted by the low levels of contamination present. Residual radioactivity levels, under either present conditions or projected future conditions, will not result in significant radiation doses to persons exposed. Modeling efforts show that future transport activity will not result in any residual radioactivity concentrations higher than those already existing. Thus, although construction of a sediment trap in lower Pueblo Canyon is a viable alternative, this effort also is unwarranted, and the no-action alternative is the preferred alternative

  15. Environmental analysis of Lower Pueblo/Lower Los Alamos Canyon, Los Alamos, New Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Ferenbaugh, R.W.; Buhl, T.E.; Stoker, A.K.; Becker, N.M.; Rodgers, J.C.; Hansen, W.R.

    1994-12-01

    The radiological survey of the former radioactive waste treatment plant site (TA-45), Acid Canyon, Pueblo Canyon, and Los Alamos Canyon found residual contamination at the site itself and in the channel and banks of Acid, Pueblo, and lower Los Alamos Canyons all the way to the Rio Grande. The largest reservoir of residual radioactivity is in lower Pueblo Canyon, which is on DOE property. However, residual radioactivity does not exceed proposed cleanup criteria in either lower Pueblo or lower Los Alamos Canyons. The three alternatives proposed are (1) to take no action, (2) to construct a sediment trap in lower Pueblo Canyon to prevent further transport of residual radioactivity onto San Ildefonso Indian Pueblo land, and (3) to clean the residual radioactivity from the canyon system. Alternative 2, to cleanup the canyon system, is rejected as a viable alternative. Thousands of truckloads of sediment would have to be removed and disposed of, and this effort is unwarranted by the low levels of contamination present. Residual radioactivity levels, under either present conditions or projected future conditions, will not result in significant radiation doses to persons exposed. Modeling efforts show that future transport activity will not result in any residual radioactivity concentrations higher than those already existing. Thus, although construction of a sediment trap in lower Pueblo Canyon is a viable alternative, this effort also is unwarranted, and the no-action alternative is the preferred alternative.

  16. Lower Red River Meadow Stream Restoration Project

    International Nuclear Information System (INIS)

    1996-05-01

    As part of a continuing effort to restore anadromous fish populations in the South Fork Clearwater River basin of Idaho, Bonneville Power Administration (BPA) proposes to fund the Lower Red River Meadow Restoration Project (Project). The Project is a cooperative effort with the Idaho Soil and Water Conservation District, Nez Perce National Forest, Idaho Department of Fish and Game (IDFG), and the Nez Perce Tribe of Idaho. The proposed action would allow the sponsors to perform stream bank stabilization, aquatic and riparian habitat improvement activities on IDFG's Red River Management Area and to secure long-term conservation contracts or agreements for conducting streambank and habitat improvement activities with participating private landowners located in the Idaho County, Idaho, study area. This preliminary Environmental Assessment (EA) examines the potential environmental effects of stabilizing the stream channel, restoring juvenile fish rearing habitat and reestablishing a riparian shrub community along the stream

  17. Modeling Nitrogen Oxides in the Lower Stratosphere

    Science.gov (United States)

    Kawa, S. Randy; Einaudi, Franco (Technical Monitor)

    2001-01-01

    This talk will focus on the status of current understanding (not a historical review) as regards modeling nitrogen oxides (NOy) in the lower stratosphere (LS). The presentation will be organized around three major areas of process understanding: 1) NOy sources, sinks, and transport to the LS, 2) NOy species partitioning, and 3) polar multiphase processes. In each area, process topics will be identified with an estimate of the degree of confidence associated with their representation in numerical models. Several exotic and/or speculative processes will also be discussed. Those topics associated with low confidence or knowledge gaps, weighted by their prospective importance in stratospheric chemical modeling, will be collected into recommendations for further study. Suggested approaches to further study will be presented for discussion.

  18. Common paediatric conditions of the lower limb.

    Science.gov (United States)

    Dobbe, Ashlee M; Gibbons, Paul J

    2017-11-01

    Growing children are susceptible to a number of disorders to their lower extremities of varying degrees of severity. The diagnosis and management of these conditions can be challenging. With musculoskeletal symptoms being one of the leading reasons for visits to general practitioners, a working knowledge of the basics of these disorders can help in the appropriate diagnosis, treatment, counselling, and specialist referral. This review covers common disorders affecting the hip, the knee and the foot. The aim is to assist general practitioners in recognising developmental norms and differentiating physiological from pathological conditions and to identify when a specialist referral is necessary. © 2017 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  19. Neuropeptides in Lower Urinary Tract (LUT) Function

    Science.gov (United States)

    Arms, Lauren; Vizzard, Margaret A.

    2014-01-01

    Numerous neuropeptide/receptor systems including vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, calcitonin gene-related peptide, substance P, neurokinin A, bradykinin, and endothelin-1 are expressed in the lower urinary tract (LUT) in both neural and non-neural (e.g., urothelium) components. LUT neuropeptide immunoreactivity is present in afferent and autonomic efferent neurons innervating the bladder and urethra and in the urothelium of the urinary bladder. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction following neural injury, inflammation and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence and pain may reflect a change in the balance of neuropeptides in bladder reflex pathways. LUT neuropeptide/receptor systems may represent potential targets for therapeutic intervention. PMID:21290237

  20. Cholesterol-lowering effect of plant sterols.

    Science.gov (United States)

    AbuMweis, Suhad S; Jones, Peter J H

    2008-12-01

    Plant sterols are plant components that have a chemical structure similar to cholesterol except for the addition of an extra methyl or ethyl group; however, plant sterol absorption in humans is considerably less than that of cholesterol. In fact, plant sterols reduce cholesterol absorption and thus reduce circulating levels of cholesterol. Earlier studies that have tested the efficacy of plant sterols as cholesterol-lowering agents incorporated plant sterols into fat spreads. Later on, plant sterols were added to other food matrices, including juices, nonfat beverages, milk and yogurt, cheese, meat, croissants and muffins, and cereal and chocolate bars. The beneficial physiologic effects of plant sterols could be further enhanced by combining them with other beneficial substances, such as olive and fish oils, fibers, and soy proteins, or with exercise. The addition of plant sterols to the diet is suggested by health experts as a safe and effective way to reduce the risk of coronary heart disease.

  1. Light water reactor lower head failure analysis

    Energy Technology Data Exchange (ETDEWEB)

    Rempe, J.L.; Chavez, S.A.; Thinnes, G.L. [EG and G Idaho, Inc., Idaho Falls, ID (United States)] [and others

    1993-10-01

    This document presents the results from a US Nuclear Regulatory Commission-sponsored research program to investigate the mode and timing of vessel lower head failure. Major objectives of the analysis were to identify plausible failure mechanisms and to develop a method for determining which failure mode would occur first in different light water reactor designs and accident conditions. Failure mechanisms, such as tube ejection, tube rupture, global vessel failure, and localized vessel creep rupture, were studied. Newly developed models and existing models were applied to predict which failure mechanism would occur first in various severe accident scenarios. So that a broader range of conditions could be considered simultaneously, calculations relied heavily on models with closed-form or simplified numerical solution techniques. Finite element techniques-were employed for analytical model verification and examining more detailed phenomena. High-temperature creep and tensile data were obtained for predicting vessel and penetration structural response.

  2. Determining lower threshold concentrations for synergistic effects.

    Science.gov (United States)

    Bjergager, Maj-Britt Andersen; Dalhoff, Kristoffer; Kretschmann, Andreas; Nørgaard, Katrine Banke; Mayer, Philipp; Cedergreen, Nina

    2017-01-01

    Though only occurring rarely, synergistic interactions between chemicals in mixtures have long been a point of focus. Most studies analyzing synergistic interactions used unrealistically high chemical concentrations. The aim of the present study is to determine the threshold concentration below which proven synergists cease to act as synergists towards the aquatic crustacean Daphnia magna. To do this, we compared several approaches and test-setups to evaluate which approach gives the most conservative estimate for the lower threshold for synergy for three known azole synergists. We focus on synergistic interactions between the pyrethroid insecticide, alpha-cypermethrin, and one of the three azole fungicides prochloraz, propiconazole or epoxiconazole measured on Daphnia magna immobilization. Three different experimental setups were applied: A standard 48h acute toxicity test, an adapted 48h test using passive dosing for constant chemical exposure concentrations, and a 14-day test. Synergy was defined as occuring in mixtures where either EC 50 values decreased more than two-fold below what was predicted by concentration addition (horizontal assessment) or as mixtures where the fraction of immobile organisms increased more than two-fold above what was predicted by independent action (vertical assessment). All three tests confirmed the hypothesis of the existence of a lower azole threshold concentration below which no synergistic interaction was observed. The lower threshold concentration, however, decreased with increasing test duration from 0.026±0.013μM (9.794±4.897μgL -1 ), 0.425±0.089μM (145.435±30.46μgL -1 ) and 0.757±0.253μM (249.659±83.44μgL -1 ) for prochloraz, propiconazole and epoxiconazole in standard 48h toxicity tests to 0.015±0.004μM (5.651±1.507μgL -1 ), 0.145±0.025μM (49.619±8.555μgL -1 ) and 0.122±0.0417μM (40.236±13.75μgL -1 ), respectively, in the 14-days tests. Testing synergy in relation to concentration addition provided

  3. Benzene formation in Titan's lower atmosphere

    Science.gov (United States)

    Plane, J. M. C.; Douglas, K.; Blitz, M. A.; Heard, D. E.; Seakins, P. W.; Feng, W.; Willacy, K.

    2017-09-01

    The most distinctive feature of Saturn's moon Titan is that it is covered in a thick haze. The haze consists of organic particles called tholins, of which benzene is thought to be an important precursor. Here we examine two pathways to form benzene. The first involves reactions on cosmic dust particles, which mostly do not ablate when entering Titan's atmosphere and accumulate in the lower atmosphere. We have shown in the laboratory that acetylene molecules stick on synthetic cosmic dust at low temperatures, and react efficiently to make benzene. The second pathway is through gas phase reactions involving radical species formed through methane photochemistry. A new lab study shows that the rates of critical reactions involving these radicals vary unexpectedly at low temperatures, leading to significant changes in important benzene precursors.

  4. Lipid-lowering effects of statins

    International Nuclear Information System (INIS)

    Ramos-Esquivel, Allan; Leon-Cespedes, Carlos

    2007-01-01

    Statins have become one of the most prescribed drugs in the world. These medications are used in the treatment of dyslipidemia and in the prevention of cardiovascular diseases. Recently, new evidence has emerged about their mechanisms of action and their pleiotropic properties, well beyond lowering cholesterol levels. This pharmacodynamic action has called the attention of many investigators who suggest their use in several diseases centered on inflammation, immune disorders and cell proliferation. Although there is wide evidence that recognizes their efficacy in several disease models, there is still a lack of studies to approve their use in clinical practice. The pharmacodynamic properties focusing on the pathophysiology that suggests their clinical use in the treatment of several diseases have been reviewed. (author) [es

  5. Light water reactor lower head failure analysis

    International Nuclear Information System (INIS)

    Rempe, J.L.; Chavez, S.A.; Thinnes, G.L.

    1993-10-01

    This document presents the results from a US Nuclear Regulatory Commission-sponsored research program to investigate the mode and timing of vessel lower head failure. Major objectives of the analysis were to identify plausible failure mechanisms and to develop a method for determining which failure mode would occur first in different light water reactor designs and accident conditions. Failure mechanisms, such as tube ejection, tube rupture, global vessel failure, and localized vessel creep rupture, were studied. Newly developed models and existing models were applied to predict which failure mechanism would occur first in various severe accident scenarios. So that a broader range of conditions could be considered simultaneously, calculations relied heavily on models with closed-form or simplified numerical solution techniques. Finite element techniques-were employed for analytical model verification and examining more detailed phenomena. High-temperature creep and tensile data were obtained for predicting vessel and penetration structural response

  6. A family of lowered isothermal models

    Science.gov (United States)

    Gieles, Mark; Zocchi, Alice

    2015-11-01

    We present a family of self-consistent, spherical, lowered isothermal models, consisting of one or more mass components, with parametrized prescriptions for the energy truncation and for the amount of radially biased pressure anisotropy. The models are particularly suited to describe the phase-space density of stars in tidally limited, mass-segregated star clusters in all stages of their life-cycle. The models extend a family of isotropic, single-mass models by Gomez-Leyton and Velazquez, of which the well-known Woolley, King and Wilson (in the non-rotating and isotropic limit) models are members. We derive analytic expressions for the density and velocity dispersion components in terms of potential and radius, and introduce a fast model solver in PYTHON (LIMEPY), that can be used for data fitting or for generating discrete samples.

  7. User experience of lower-limb orthosis.

    Science.gov (United States)

    Yang, Bing-Shiang; Chen, Yen-Wan; Tong, Ji-Rou

    2017-06-09

    If an assistive device is not acceptable to the user, it will not achieve efficacy and would be resource-wasting. This study employed in-depth interviews to understand what users' individual activities of daily living, problems of using orthoses, and considerations for selecting orthoses are. We conducted qualitative interviews with 35 lower-limb orthosis users, and semi-structured interviews were applied in this study. We analyzed the interview data from transcripts, through coding and concepts, to theories based on grounded theory. The results showed that problems of using orthoses are mostly related to activities of daily living of the user and user's expectation. Therefore, in order to enhance its efficacy and use intention, the design and prescribing process of orthoses need to address the problems in the light of activities of daily living and user education.

  8. Residual impairment after lower extremity fracture

    DEFF Research Database (Denmark)

    Faergemann, C; Frandsen, P A; Röck, N D

    1998-01-01

    In a prospective follow-up study of 158 consecutive patients 18 to 64 years old with unilateral lower extremity fracture, our aim was to disclose the impairment and disability 6 months after the injury. The patients were interviewed within 1 week after the trauma, and all patients returned...... the functional status before the injury. Additionally, three major aspects of impairments were measured 6 months after the fractures: range of motion, muscle strength, and pain. Most patients had a significantly higher SIP score 6 months after the fracture(s) than pretraumatically. The mean overall SIP score...... was 2.7 pretraumatically and 8.7 6 months posttraumatically. Major deficits in range of motion was observed, especially in the ankle joint. Additionally, loss of muscle strength was observed in the thigh and calf muscles in one fourth of the patients. Only low levels of residual pain were reported after...

  9. Aquatic macroinvertebrates of the lower Missouri River

    Science.gov (United States)

    Poulton, Barry C.

    2010-01-01

    The U.S. Geological Survey (USGS) Columbia Environmental Research Center (CERC), in cooperation with the U.S. Environmental Protection Agency (USEPA), the U.S. Fish & Wildlife Service (USFWS), and the Missouri Department of Natural Resources (MDNR), has been conducting research on the aquatic macroinvertebrates of the lower Missouri River since the mid-1990s. This research was initiated in response to the need for comprehensive characterization of biological communities inhabiting aquatic habitats in large river systems that have historically been poorly studied. The USGS Status and Trends of Biological Resources Program provided partial funding for pilot studies that began in 1993 when the CERC was part of the USFWS. The purpose of this fact sheet is to provide stakeholders, scientists, management, and the general public with a basic summary of results from studies conducted by the CERC since that time period.

  10. PWR upper/lower internals shield

    Energy Technology Data Exchange (ETDEWEB)

    Homyk, W.A. [Indian Point Station, Buchanan, NY (United States)

    1995-03-01

    During refueling of a nuclear power plant, the reactor upper internals must be removed from the reactor vessel to permit transfer of the fuel. The upper internals are stored in the flooded reactor cavity. Refueling personnel working in containment at a number of nuclear stations typically receive radiation exposure from a portion of the highly contaminated upper intervals package which extends above the normal water level of the refueling pool. This same issue exists with reactor lower internals withdrawn for inservice inspection activities. One solution to this problem is to provide adequate shielding of the unimmersed portion. The use of lead sheets or blankets for shielding of the protruding components would be time consuming and require more effort for installation since the shielding mass would need to be transported to a support structure over the refueling pool. A preferable approach is to use the existing shielding mass of the refueling pool water. A method of shielding was devised which would use a vacuum pump to draw refueling pool water into an inverted canister suspended over the upper internals to provide shielding from the normally exposed components. During the Spring 1993 refueling of Indian Point 2 (IP2), a prototype shield device was demonstrated. This shield consists of a cylindrical tank open at the bottom that is suspended over the refueling pool with I-beams. The lower lip of the tank is two feet below normal pool level. After installation, the air width of the natural shielding provided by the existing pool water. This paper describes the design, development, testing and demonstration of the prototype device.

  11. Lower limb joint replacement in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Clement Nicholas D

    2012-06-01

    Full Text Available Abstract Introduction There is limited literature regarding the peri-operative and surgical management of patients with rheumatoid disease undergoing lower limb arthroplasty. This review article summarises factors involved in the peri-operative management of major lower limb arthroplasty surgery for patients with rheumatoid arthritis. Methods We performed a search of the medical literature, using the PubMed search engine (http://www.pubmed.gov. We used the following terms: ‘rheumatoid’ ‘replacement’ ‘arthroplasty’ and ‘outcome’. Findings The patient should be optimised pre-operatively using a multidisciplinary approach. The continued use of methotrexate does not increase infection risk, and aids recovery. Biologic agents should be stopped pre-operatively due the increased infection rate. Patients should be made aware of the increased risk of infection and periprosthetic fracture rates associated with their disease. The surgical sequence is commonly hip, knee and then ankle. Cemented total hip replacement (THR and total knee replacement (TKR have superior survival rates over uncemented components. The evidence is not clear regarding a cruciate sacrificing versus retaining in TKR, but a cruciate sacrificing component limits the risk early instability and potential revision. Patella resurfacing as part of a TKR is associated with improved outcomes. The results of total ankle replacement remain inferior to THR and TKR. RA patients achieve equivalent pain relief, but their rehabilitation is slower and their functional outcome is not as good. However, the key to managing these complicated patients is to work as part of a multidisciplinary team to optimise their outcome.

  12. Evaporite karst of northern lower Michigan

    Science.gov (United States)

    Black, T.J.

    1997-01-01

    Michigan has three main zones of evaporite karst: collapse breccia in Late Silurian deposits of the Mackinac Straits region; breccia, collapse sinks, and mega-block collapse in Middle Devonian deposits of Northern Lower Michigan, which overlaps the preceding area; and areas of soil swallows in sinks of Mississippian deposits between Turner and Alabaster in Arenac and Iosco counties, and near Grand Rapids in Kent County. The author has focused his study on evaporite karst of the Middle Devonian deposits. The Middle Devonian depos its are the Detroit River Group: a series consisting of limestone, dolomite, shale, salt, gypsum, and anhydrite. The group occurs from subcrop, near the surface, to nearly 1400 feet deep from the northern tip of the Southern Peninsula to the south edge of the "solution front" Glacial drift is from zero to 350 feet thick. Oil and gas exploration has encountered some significant lost-circulation zones throughout the area. Drilling without fluid returns, casing-seal failures, and lost holes are strong risks in some parts of the region. Lost fluid returns near the top of the group in nearby areas indicate some karst development shortly after deposition. Large and irregular lost-circulation zones, linear and patch trends of large sink holes, and 0.25 mile wide blocks of down-dropped land in the northern Lower Peninsula of Michigan were caused by surface- and ground-water movement along faults into the Detroit River Group. Glaciation has removed some evidence of the karst area at the surface. Sinkhole development, collapse valleys, and swallows developed since retreat of the glacier reveal an active solution front in the Detroit River Group.

  13. Lipid-lowering therapy: who can benefit

    Directory of Open Access Journals (Sweden)

    Lewis S

    2011-08-01

    Full Text Available Sandra J LewisNorthwest Cardiovascular Institute, Portland, OR, USAAbstract: Cardiovascular disease (CVD is the leading cause of death in the US. Despite the decline in CVD-associated mortality rates in recent years, coronary heart disease (CHD still causes one in every six deaths in this country. Because most CHD risk factors are modifiable (eg, smoking, hypertension, obesity, onset of type 2 diabetes, and dyslipidemia, cardiovascular risk can be reduced by timely and appropriate interventions, such as smoking cessation, diet and lifestyle changes, and lipid-modifying therapy. Dyslipidemia, manifested by elevated low-density lipoprotein cholesterol (LDL-C, is central to the development and progression of athe