%0 Journal Article %J J Alzheimers Dis %D 2018 %T Differential Pattern of Phospholipid Profile in the Temporal Cortex from E280A-Familiar and Sporadic Alzheimer's Disease Brains. %A Villamil-Ortiz, Javier Gustavo %A Barrera-Ocampo, Alvaro %A Arias-Londoño, Julián David %A Villegas, Andrés %A Lopera, Francisco %A Cardona-Gómez, Gloria Patricia %K Adult %K Aged %K Aged, 80 and over %K Alanine %K Alzheimer Disease %K Analysis of Variance %K Fatty Acids %K Female %K Gene Expression Regulation %K Glutamic Acid %K Humans %K Lysophosphatidylcholines %K Male %K Mass Spectrometry %K Middle Aged %K Mutation %K Phosphatidylethanolamines %K Phospholipids %K Presenilin-1 %K Temporal Lobe %X

Lipids are considered important factors in the pathogenesis of Alzheimer's disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains.

%B J Alzheimers Dis %V 61 %P 209-219 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29125487?dopt=Abstract %R 10.3233/JAD-170554 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Dysregulation and Dislocation of SFPQ Disturbed DNA Organization in Alzheimer's Disease and Frontotemporal Dementia. %A Lu, Jing %A Shu, Runzhe %A Zhu, Yan %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Animals %K Brain %K Cell Line, Tumor %K DNA Damage %K Female %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Male %K Mice %K PTB-Associated Splicing Factor %K tau Proteins %K Translocation, Genetic %X

SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD.

%B J Alzheimers Dis %V 61 %P 1311-1321 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376859?dopt=Abstract %R 10.3233/JAD-170659 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer's Disease and Brain Aging. %A Hasegawa, Yu %A Toyama, Kensuke %A Uekawa, Ken %A Ichijo, Hidenori %A Kim-Mitsuyama, Shokei %K Aging %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Avoidance Learning %K Disease Models, Animal %K Gene Expression Regulation %K MAP Kinase Kinase Kinase 5 %K MAP Kinase Signaling System %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Presenilin-1 %K Reaction Time %X

To examine the role of ASK1 in Alzheimer's disease (AD), we generated 5XFAD mice deficient in ASK1 and investigated the characteristics of old 5XFAD and wild-type mice with ASK1 deficiency. ASK1 deficiency improved cognitive function in 24-month-old 5XFAD mice, which was associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade seems to play some role in the pathogenesis of AD in mice. In 24-month-old wild-type mice, ASK1 deficiency increased cerebral vasoreactivity to acetazolamide and significantly reduced brain soluble Aβ, which were also associated with the reduction of phosphorylated p38. Thus, ASK1/p38 cascade may contribute to brain aging of wild-type mice. Collectively, our present results provided the evidence suggesting the involvement of ASK1/p38 cascade in AD and brain aging.

%B J Alzheimers Dis %V 61 %P 259-263 %8 2018 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/29154282?dopt=Abstract %R 10.3233/JAD-170645 %0 Journal Article %J J Alzheimers Dis %D 2018 %T VEGFR1 and VEGFR2 in Alzheimer's Disease. %A Harris, Rachel %A Miners, James Scott %A Allen, Shelley %A Love, Seth %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Brain %K Case-Control Studies %K Endothelial Cells %K Female %K Gene Expression Regulation %K Humans %K Male %K Middle Aged %K Neovascularization, Pathologic %K RNA, Messenger %K Signal Transduction %K Vascular Endothelial Growth Factor A %K Vascular Endothelial Growth Factor Receptor-1 %K Vascular Endothelial Growth Factor Receptor-2 %X

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-β, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

%B J Alzheimers Dis %V 61 %P 741-752 %8 2018 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29226875?dopt=Abstract %R 10.3233/JAD-170745 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Humanin Specifically Interacts with Amyloid-β Oligomers and Counteracts Their in vivo Toxicity. %A Romeo, Margherita %A Stravalaci, Matteo %A Beeg, Marten %A Rossi, Alessandro %A Fiordaliso, Fabio %A Corbelli, Alessandro %A Salmona, Mario %A Gobbi, Marco %A Cagnotto, Alfredo %A Diomede, Luisa %K Amyloid beta-Peptides %K Animals %K Animals, Genetically Modified %K Caenorhabditis elegans %K Caenorhabditis elegans Proteins %K Circular Dichroism %K Disease Models, Animal %K Dose-Response Relationship, Drug %K Gene Expression Regulation %K Humans %K Intracellular Signaling Peptides and Proteins %K Microscopy, Atomic Force %K Microscopy, Electron, Transmission %K Neprilysin %K Paralysis %K Peptide Fragments %K Surface Plasmon Resonance %X

The 24-residue peptide humanin (HN) has been proposed as a peptide-based inhibitor able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously, HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting the Aβ-induced toxicity. Whether these peptides interact directly with Aβ, particularly with the soluble oligomeric assemblies, remains largely unknown. We here investigated the ability of HN and HNG to interact directly with highly aggregating Aβ42, and interfere with the formation and toxicity of its oligomers. Experiments were run in cell-free conditions and in vivo in a transgenic C. elegans strain in which the Aβ toxicity was specifically due to oligomeric species. Thioflavin-T assay indicated that both HN and HNG delay the formation and reduce the final amount of Aβ42 fibrils. In vitro surface plasmon resonance studies indicated that they interact with Aβ42 oligomers favoring the formation of amorphous larger assemblies, observed with turbidity and electron microscopy. In vivo studies indicated that both HN and HNG decrease the relative abundance of A11-positive prefibrillar oligomers as well as OC-positive fibrillar oligomers and had similar protective effects. However, while HN possibly decreased the oligomers by promoting their assembly into larger aggregates, the reduction of oligomers caused by HNG can be ascribed to a marked decrease of the total Aβ levels, likely the consequence of the HNG-induced overexpression of the Aβ-degrading enzyme neprilysin. These findings provide information on the mechanisms underlying the anti-oligomeric effects of HN and HNG and illustrate the role of S14G substitution in regulating the in vivo mechanism of action.

%B J Alzheimers Dis %V 57 %P 857-871 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28282805?dopt=Abstract %R 10.3233/JAD-160951 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Palmitate Increases β-site AβPP-Cleavage Enzyme 1 Activity and Amyloid-β Genesis by Evoking Endoplasmic Reticulum Stress and Subsequent C/EBP Homologous Protein Activation. %A Marwarha, Gurdeep %A Rostad, Stephen %A Lilek, Jaclyn %A Kleinjan, Mason %A Schommer, Jared %A Ghribi, Othman %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Aspartic Acid Endopeptidases %K Cell Line, Tumor %K Dose-Response Relationship, Drug %K Endoplasmic Reticulum Stress %K Gene Expression Regulation %K Hippocampus %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Neuroblastoma %K Palmitates %K RNA, Messenger %K Signal Transduction %K Transcription Factor CHOP %K Transcription Factors %K Transfection %X

Epidemiological studies implicate diets rich in saturated free fatty acids (sFFA) as a potential risk factor for developing Alzheimer's disease (AD). In particular, high plasma levels of the sFFA palmitic acid (palmitate) were shown to inversely correlate with cognitive function. However, the cellular mechanisms by which sFFA may increase the risk for AD are not well known. Endoplasmic reticulum (ER) stress has emerged as one of the signaling pathways initiating and fostering the neurodegenerative changes in AD by increasing the aspartyl protease β-site AβPP cleaving enzyme 1 (BACE1) and amyloid-β (Aβ) genesis. In this study, we determined the extent to which palmitate increases BACE1 and Aβ levels in vitro and in vivo as well as the potential role of ER stress as cellular mechanism underlying palmitate effects. We demonstrate, in palmitate-treated SH-SY5Y neuroblastoma cells and in the hippocampi of palmitate-enriched diet-fed mice, that palmitate evokes the activation of the C/EBP Homologous Protein (CHOP), a transcription factor that is specifically responsive to ER stress. Induction of CHOP expression is associated with increased BACE1 mRNA, protein and activity levels, and subsequent enhanced amyloidogenic processing of amyloid-β protein precursor (AβPP) that culminates in a substantial increase in Aβ genesis. We further show that CHOP is an indispensable molecular mediator of palmitate-induced upregulation in BACE1 activity and Aβ genesis. Indeed, we show that Chop-/- mice and CHOP knocked-down SH-SY5Y neuroblastoma cells do not exhibit the same commensurate degree of palmitate-induced increase in BACE1 expression levels and Aβ genesis.

%B J Alzheimers Dis %V 57 %P 907-925 %8 2017 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/28304295?dopt=Abstract %R 10.3233/JAD-161130 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer's Disease. %A Guillot, Florence %A Kemppainen, Susanna %A Lavasseur, Gregoire %A Miettinen, Pasi O %A Laroche, Serge %A Tanila, Heikki %A Davis, Sabrina %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mitogen-Activated Protein Kinase Kinases %K Mutation %K Oncogene Protein v-akt %K Phosphatidylinositol 3-Kinases %K Presenilin-1 %K Signal Transduction %X

Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer's disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer's disease.

%B J Alzheimers Dis %V 51 %P 1157-73 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26923018?dopt=Abstract %R 10.3233/JAD-150926 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer's Disease Mouse Model. %A LeVault, Kelsey R %A Tischkau, Shelley A %A Brewer, Gregory J %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Brain %K Chromatography, High Pressure Liquid %K Chronobiology Disorders %K Disease Models, Animal %K Gene Expression Regulation %K Glutathione %K Glutathione Disulfide %K Humans %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K NADP %K Nitric Oxide Synthase Type II %K Oxidation-Reduction %X

It is unclear whether pre-symptomatic Alzheimer's disease (AD) causes circadian disruption or whether circadian disruption accelerates AD pathogenesis. In order to examine the sensitivity of learning and memory to circadian disruption, we altered normal lighting phases by an 8 h shortening of the dark period every 3 days (jet lag) in the APPSwDI NOS2-/- model of AD (AD-Tg) at a young age (4-5 months), when memory is not yet affected compared to non-transgenic (non-Tg) mice. Analysis of activity in 12-12 h lighting or constant darkness showed only minor differences between AD-Tg and non-Tg mice. Jet lag greatly reduced activity in both genotypes during the normal dark time. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to jet lag. However, memory 3 days after training was impaired in both genotypes. Jet lag caused a decrease of glutathione (GSH) levels that tended to be more pronounced in AD-Tg than in non-Tg brains and an associated increase in NADH levels in both genotypes. Lower brain GSH levels after jet lag correlated with poor performance on the maze. These data indicate that the combination of the environmental stress of circadian disruption together with latent stress of the mutant amyloid and NOS2 knockout contributes to cognitive deficits that correlate with lower GSH levels.

%B J Alzheimers Dis %V 49 %P 301-16 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484899?dopt=Abstract %R 10.3233/JAD-150026 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Different Expression Patterns of Amyloid-β Protein Precursor Secretases in Human and Mouse Hippocampal Neurons: A Potential Contribution to Species Differences in Neuronal Susceptibility to Amyloid-β Pathogenesis. %A Xu, Zhi-Qiang %A Huang, Huang %A Chen, Ya-Li %A Gao, Yun-Ying %A Xu, Jun %A Marshall, Charles %A Cai, Zhi-You %A Xiao, Ming %K ADAM10 Protein %K Amyloid beta-Peptides %K Amyloid Precursor Protein Secretases %K Animals %K Antibodies %K Aspartic Acid Endopeptidases %K Cell Count %K Dose-Response Relationship, Drug %K Female %K Gene Expression Regulation %K Hippocampus %K Humans %K Low Density Lipoprotein Receptor-Related Protein-1 %K Male %K Mice %K Mice, Transgenic %K Middle Aged %K Mutation %K Neurons %K Peptide Fragments %K Presenilin-1 %K Species Specificity %K Time Factors %X

Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer's disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α-secretase, and its neuroprotective products soluble AβPPα, but low levels of amyloidogenic β-secretase and γ-secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ-secretase, but not α-secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α-secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α-secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α-secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD.

%B J Alzheimers Dis %V 51 %P 179-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836155?dopt=Abstract %R 10.3233/JAD-150634 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Differential Regulation of N-Methyl-D-Aspartate Receptor Subunits is an Early Event in the Actions of Soluble Amyloid-β(1-40) Oligomers on Hippocampal Neurons. %A Chang, Lirong %A Zhang, Yali %A Liu, Jinping %A Song, Yizhi %A Lv, Angchu %A Li, Yan %A Zhou, Wei %A Yan, Zhen %A Almeida, Osborne F X %A Wu, Yan %K Amyloid beta-Peptides %K Animals %K Animals, Newborn %K Cells, Cultured %K Dendrites %K Gene Expression Regulation %K Hippocampus %K Male %K Neurons %K Peptide Fragments %K Phosphorylation %K Rats %K Rats, Wistar %K Receptors, N-Methyl-D-Aspartate %X

Synaptic dysfunction during early stages of Alzheimer's disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of denritic and synaptic pTyr1472-GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325-GluN2A puncta densities and increased synaptic pTyr1325-GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472-GluN2B protein levels but did not influence GluN2A and pTyr1325-GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions.

%B J Alzheimers Dis %V 51 %P 197-212 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836185?dopt=Abstract %R 10.3233/JAD-150942 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Early in vivo Effects of the Human Mutant Amyloid-β Protein Precursor (hAβPPSwInd) on the Mouse Olfactory Bulb. %A Rusznák, Zoltán %A Kim, Woojin Scott %A Hsiao, Jen-Hsiang T %A Halliday, Glenda M %A Paxinos, George %A Fu, YuHong %K Age Factors %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Cell Proliferation %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Ki-67 Antigen %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurogenesis %K Neurons %K Olfactory Bulb %K Piriform Cortex %X

The amyloid-β protein precursor (AβPP) has long been linked to Alzheimer's disease (AD). Using J20 mice, which express human AβPP with Swedish and Indiana mutations, we studied early pathological changes in the olfactory bulb. The presence of AβPP/amyloid-β (Aβ) was examined in mice aged 3 months (before the onset of hippocampal Aβ deposition) and over 5 months (when hippocampal Aβ deposits are present). The number of neurons, non-neurons, and proliferating cells was assessed using the isotropic fractionator method. Our results demonstrate that although AβPP is overexpressed in some of the mitral cells, widespread Aβ deposition and microglia aggregates are not prevalent in the olfactory bulb. The olfactory bulbs of the younger J20 group harbored significantly fewer neurons than those of the age-matched wild-type mice (5.57±0.13 million versus 6.59±0.36 million neurons; p = 0.011). In contrast, the number of proliferating cells was higher in the young J20 than in the wild-type group (i.e., 6617±425 versus 4455±623 cells; p = 0.011). A significant increase in neurogenic activity was also observed in the younger J20 olfactory bulb. In conclusion, our results indicate that (1) neurons participating in the mouse olfactory function overexpress AβPP; (2) the cellular composition of the young J20 olfactory bulb is different from that of wild-type littermates; (3) these differences may reflect altered neurogenic activity and/or delayed development of the J20 olfactory system; and (4) AβPP/Aβ-associated pathological changes that take place in the J20 hippocampus and olfactory bulb are not identical.

%B J Alzheimers Dis %V 49 %P 443-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484907?dopt=Abstract %R 10.3233/JAD-150368 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Anserine/Carnosine Supplementation on Verbal Episodic Memory in Elderly People. %A Hisatsune, Tatsuhiro %A Kaneko, Jun %A Kurashige, Hiroki %A Cao, Yuan %A Satsu, Hideo %A Totsuka, Mamoru %A Katakura, Yoshinori %A Imabayashi, Etsuko %A Matsuda, Hiroshi %K Adult %K Aged %K Aging %K Anserine %K Brain %K Carnosine %K Cytokines %K Dietary Supplements %K Double-Blind Method %K Female %K Gene Expression Regulation %K Humans %K Image Processing, Computer-Assisted %K Male %K Memory, Episodic %K Middle Aged %K Neuropsychological Tests %K Oligonucleotide Array Sequence Analysis %K Verbal Learning %X

Our goal in this study was to determine whether or not anserine/carnosine supplementation (ACS) is capable of preserving cognitive function of elderly people. In a double-blind randomized controlled trial, volunteers were randomly assigned to an ACS or placebo group at a 1:1 ratio. The ACS group took 1.0 g of an anserine/carnosine (3:1) formula daily for 3 months. Participants were evaluated by psychological tests before and after the 3-month supplementation period. Thirty-nine healthy elderly volunteers (60-78 years old) completed the follow-up tests. Among the tests, delayed recall verbal memory assessed by the Wechsler Memory Scale-Logical Memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0128). Blood analysis revealed a decreased secretion of inflammatory cytokines, including CCL-2 and IL-8, in the ACS group. MRI analysis using arterial spin labeling showed a suppression in the age-related decline in brain blood flow in the posterior cingulate cortex area in the ACS group, compared to the placebo group (p = 0.0248). In another randomized controlled trial, delayed recall verbal memory showed significant preservation in the ACS group, compared to the placebo group (p = 0.0202). These results collectively suggest that ACS may preserve verbal episodic memory and brain perfusion in elderly people, although further study is needed.

%B J Alzheimers Dis %V 50 %P 149-59 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26682691?dopt=Abstract %R 10.3233/JAD-150767 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control. %A Huang, Chunxia %A Ng, Olivia Tsz-Wa %A Ho, Yuen-Shan %A Irwin, Michael Garnet %A Chang, Raymond Chuen-Chung %A Wong, Gordon Tin-Chun %K Amyloid beta-Peptides %K Analysis of Variance %K Anesthetics, Intravenous %K Animals %K Body Temperature %K Brain %K Gene Expression Regulation %K Glycogen Synthase Kinase 3 beta %K Hypothermia, Induced %K Male %K Peptide Fragments %K Phosphorylation %K Propofol %K Rats %K Rats, Sprague-Dawley %K Signal Transduction %K tau Proteins %X

Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.

%B J Alzheimers Dis %V 51 %P 213-26 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836157?dopt=Abstract %R 10.3233/JAD-150645 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Gx-50 Inhibits Neuroinflammation via α7 nAChR Activation of the JAK2/STAT3 and PI3K/AKT Pathways. %A Shi, Shi %A Liang, Dongli %A Bao, Min %A Xie, Yilin %A Xu, Wangjie %A Wang, Lianyun %A Wang, Zhaoxia %A Qiao, Zhongdong %K Acrylamides %K alpha7 Nicotinic Acetylcholine Receptor %K Amyloid beta-Peptides %K Analysis of Variance %K Animals %K Anti-Inflammatory Agents %K Cell Line, Transformed %K Cytokines %K Enzyme Inhibitors %K Enzyme-Linked Immunosorbent Assay %K Gene Expression Regulation %K Janus Kinase 2 %K Mice %K Microglia %K Phosphatidylinositol 3-Kinases %K Protein Binding %K RNA, Messenger %K Signal Transduction %X

Recent studies have revealed that the α7 nicotinic acetylcholine receptor (α7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer's disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α7 nAChR activity, which might be a successful therapeutic target against AD.

%B J Alzheimers Dis %V 50 %P 859-71 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836188?dopt=Abstract %R 10.3233/JAD-150963 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Hippocampal Lipid Homeostasis in APP/PS1 Mice is Modulated by a Complex Interplay Between Dietary DHA and Estrogens: Relevance for Alzheimer's Disease. %A Díaz, Mario %A Fabelo, Noemí %A Casañas-Sánchez, Verónica %A Marin, Raquel %A Gómez, Tomás %A Quinto-Alemany, David %A Pérez, José A %K Acyl Coenzyme A %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Analysis of Variance %K Animals %K Disease Models, Animal %K Docosahexaenoic Acids %K Dose-Response Relationship, Drug %K Estrogens %K Gene Expression Regulation %K Hippocampus %K Homeostasis %K Humans %K Lipid Metabolism %K Mice %K Mice, Transgenic %K Mutation %K Presenilin-1 %K RNA, Messenger %X

Current evidence suggests that lipid homeostasis in the hippocampus is affected by different genetic, dietary, and hormonal factors, and that its deregulation may be associated with the onset and progression of Alzheimer's disease (AD). However, the precise levels of influence of each of these factors and their potential interactions remain largely unknown, particularly during neurodegenerative processes. In the present study, we have performed multifactorial analyses of the combined effects of diets containing different doses of docosahexaenoic acid (DHA), estrogen status (ovariectomized animals receiving vehicle or 17β-estradiol), and genotype (wild-type or transgenic APP/PS1 mice) in hippocampal lipid profiles. We have observed that the three factors affect lipid classes and fatty acid composition to different extents, and that strong interactions between these factors exist. The most aberrant lipid profiles were observed in APP/PS1 animals receiving DHA-poor diets and deprived of estrogens. Conversely, wild-type animals under a high-DHA diet and receiving estradiol exhibited a lipid profile that closely resembled that of the hippocampus of control animals. Interestingly, though the lipid signatures of APP/PS1 hippocampi markedly differed from wild-type, administration of a high-DHA diet in the presence of estrogens gave rise to a lipid profile that approached that of control animals. Paralleling changes in lipid composition, patterns of gene expression of enzymes involved in lipid biosynthesis were also altered and affected by combination of experimental factors. Overall, these results indicate that hippocampal lipid homeostasis is strongly affected by hormonal and dietary conditions, and that manipulation of these factors might be incorporated in AD therapeutics.

%B J Alzheimers Dis %V 49 %P 459-81 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519437?dopt=Abstract %R 10.3233/JAD-150470 %0 Journal Article %J J Alzheimers Dis %D 2016 %T LRP/LR Antibody Mediated Rescuing of Amyloid-β-Induced Cytotoxicity is Dependent on PrPc in Alzheimer's Disease. %A Pinnock, Emma C %A Jovanovic, Katarina %A Pinto, Maxine G %A Ferreira, Eloise %A Dias, Bianca Da Costa %A Penny, Clement %A Knackmuss, Stefan %A Reusch, Uwe %A Little, Melvyn %A Schatzl, Hermann M %A Weiss, Stefan F T %K Amyloid beta-Peptides %K Animals %K Antibodies %K Cell Line, Transformed %K Cell Survival %K Flow Cytometry %K Gene Expression Regulation %K Humans %K Mice %K Peptide Fragments %K Prions %K Receptors, Laminin %K Transfection %X

The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP-/-  cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP-/-  HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 645-57 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484914?dopt=Abstract %R 10.3233/JAD-150482 %0 Journal Article %J J Alzheimers Dis %D 2016 %T A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam. %A Stockburger, Carola %A Miano, Davide %A Baeumlisberger, Marion %A Pallas, Thea %A Arrey, Tabiwang N %A Karas, Michael %A Friedland, Kristina %A Müller, Walter E %K Adenosine Triphosphate %K Aging %K Alzheimer Disease %K Animals %K Brain %K Cell Line %K Cognition Disorders %K Female %K GAP-43 Protein %K Gene Expression Regulation %K Humans %K Male %K Membrane Glycoproteins %K Mitochondria %K Mitochondrial Membrane Transport Proteins %K Nerve Tissue Proteins %K Nitroprusside %K Nootropic Agents %K Piracetam %K Proteomics %K Rats %K RNA, Small Interfering %X

Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

%B J Alzheimers Dis %V 50 %P 201-15 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639968?dopt=Abstract %R 10.3233/JAD-150687 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Morroniside-Induced PP2A Activation Antagonizes Tau Hyperphosphorylation in a Cellular Model of Neurodegeneration. %A Yang, Cui-cui %A Kuai, Xue-xian %A Gao, Wen-bin %A Yu, Jian-chun %A Wang, Qi %A Li, Lin %A Zhang, Lan %K Analysis of Variance %K Cell Line %K Enzyme Inhibitors %K Gene Expression Regulation %K Glycogen Synthase Kinase 3 beta %K Glycosides %K HEK293 Cells %K Humans %K Neuroblastoma %K Okadaic Acid %K Phosphorylation %K Protein Phosphatase 2 %K RNA, Small Interfering %K tau Proteins %K Transfection %K Tyrosine %X

BACKGROUND: An accumulation of hyperphosphorylated tau in the brain is a hallmark of Alzheimer's disease (AD). Deficits in protein phosphatase 2A (PP2A) are associated with tau hyperphosphorylation in AD.

OBJECTIVE: To investigate the effects of morroniside (MOR), isolated from Cornus officinalis, on tau hyperphosphorylation and its underlying mechanisms related to PP2A.

METHODS: SK-N-SH cells were pretreated with 50-200 μM MOR for 24 h followed by 20 nM okadaic acid (OA) for 6 h. PP2Ac siRNA was transfected into HEK293 cells to determine the direct interaction of MOR with PP2A. Western blotting was used to measure the expression of proteins and enzymes. PP2A activity was measured by molybdenum blue spectrophotometry.

RESULTS: Pretreatment with MOR improved the cellular morphological damage and inhibited tau hyperphosphorylation in SK-N-SH cells induced by OA, a PP2A inhibitor. Moreover, MOR increased PP2A activity, concurrent with a decrease in the expression of demethylated PP2A at Leu309 and phosphorylated PP2A at Tyr307. MOR decreased protein phosphatase methylesterase 1 (PME-1) expression and the ratio of PME-1/leucine carboxyl methyltransferase 1 (LCMT-1). Furthermore, MOR treatment decreased the phosphorylation of Src at Tyr416, which regulates the phosphorylation of PP2A. MOR had no effect on PP2Ac expression and tau hyperphosphorylation in PP2Ac siRNA-transfected cells.

CONCLUSION: MOR attenuated OA-induced tau hyperphosphorylation via PP2A activation, and its mechanism might be related to the regulation of PP2Ac post-translational modification and upstream enzymes such as Src and PME-1.

%B J Alzheimers Dis %V 51 %P 33-44 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836014?dopt=Abstract %R 10.3233/JAD-150728 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease. %A Banerjee, Priyanjalee %A Sahoo, Arghyadip %A Anand, Shruti %A Bir, Aritri %A Chakrabarti, Sasanka %K Administration, Oral %K Aging %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Amyloid Precursor Protein Secretases %K Animals %K Benzoates %K Brain %K Ferritins %K Gene Expression Regulation %K Iron %K Iron Chelating Agents %K Neprilysin %K NF-kappa B %K Oxidative Stress %K Peptide Fragments %K Protein Carbonylation %K Rats %K Rats, Wistar %K Receptors, Transferrin %K Spectrophotometry %K Triazoles %X

The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.

%B J Alzheimers Dis %V 49 %P 681-93 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484920?dopt=Abstract %R 10.3233/JAD-150514 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Overexpression of Metallothionein-1 Modulates the Phenotype of the Tg2576 Mouse Model of Alzheimer's Disease. %A Manso, Yasmina %A Comes, Gemma %A López-Ramos, Juan C %A Belfiore, Mónica %A Molinero, Amalia %A Giralt, Mercedes %A Carrasco, Javier %A Adlard, Paul A %A Bush, Ashley I %A Delgado-García, José María %A Hidalgo, Juan %K Age Factors %K Alzheimer Disease %K Amyloid beta-Protein Precursor %K Animals %K Anxiety %K Disease Models, Animal %K Exploratory Behavior %K Female %K Gene Expression Regulation %K Humans %K Male %K Matrix Metalloproteinase 16 %K Maze Learning %K Metallothionein %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Motor Activity %K Mutation %K Phenotype %K Psychomotor Disorders %X

Alzheimer's disease (AD) is the most commonly diagnosed dementia, where signs of neuroinflammation and oxidative stress are prominent. In this study we intend to further characterize the roles of the antioxidant, anti-inflammatory, and heavy metal binding protein, metallothionein-1 (MT-1), by crossing Mt1 overexpressing mice with a well-known mouse model of AD, Tg2576 mice, which express the human amyloid-β protein precursor (hAβPP) with the Swedish K670N/M671L mutations. Mt1 overexpression increased overall perinatal survival, but did not affect significantly hAβPP-induced mortality and weight loss in adult mice. Amyloid plaque burden in ∼14-month-old mice was increased by Mt1 overexpression in the hippocampus but not the cortex. Despite full length hAβPP levels and amyloid plaques being increased by Mt1 overexpression in the hippocampus of both sexes, oligomeric and monomeric forms of Aβ, which may contribute more to toxicity, were decreased in the hippocampus of females and increased in males. Several behavioral traits such as exploration, anxiety, and learning were altered in Tg2576 mice to various degrees depending on the age and the sex. Mt1 overexpression ameliorated the effects of hAβPP on exploration in young females, and potentiated those on anxiety in old males, and seemed to improve the rate of spatial learning (Morris water maze) and the learning elicited by a classical conditioning procedure (eye-blink test). These results clearly suggest that MT-1 may be involved in AD pathogenesis.

%B J Alzheimers Dis %V 51 %P 81-95 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836194?dopt=Abstract %R 10.3233/JAD-151025 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Spatial Memory Impairment is Associated with Intraneural Amyloid-β Immunoreactivity and Dysfunctional Arc Expression in the Hippocampal-CA3 Region of a Transgenic Mouse Model of Alzheimer's Disease. %A Morin, Jean-Pascal %A Cerón-Solano, Giovanni %A Velázquez-Campos, Giovanna %A Pacheco-López, Gustavo %A Bermúdez-Rattoni, Federico %A Díaz-Cintra, Sofía %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloid beta-Protein Precursor %K Animals %K Benzeneacetamides %K CA3 Region, Hippocampal %K Cytoskeletal Proteins %K Disease Models, Animal %K Gene Expression Regulation %K Humans %K Maze Learning %K Memory Disorders %K Mice %K Mice, Transgenic %K Mutation %K Nerve Tissue Proteins %K Neurons %K Presenilin-1 %K Pyridines %K tau Proteins %X

Dysfunction of synaptic communication in cortical and hippocampal networks has been suggested as one of the neuropathological hallmarks of the early stages of Alzheimer's disease (AD). Also, several lines of evidence have linked disrupted levels of activity-regulated cytoskeletal associated protein (Arc), an immediate early gene product that plays a central role in synaptic plasticity, with AD "synaptopathy". The mapping of Arc expression patterns in brain networks has been extensively used as a marker of memory-relevant neuronal activity history. Here we evaluated basal and behavior-induced Arc expression in hippocampal networks of the 3xTg-AD mouse model of AD. The basal percentage of Arc-expressing cells in 10-month-old 3xTg-AD mice was higher than wild type in CA3 (4.88% versus 1.77% , respectively) but similar in CA1 (1.75% versus 2.75% ). Noteworthy, this difference was not observed at 3 months of age. Furthermore, although a Morris water maze test probe induced a steep (∼4-fold) increment in the percentage of Arc+ cells in the CA3 region of the 10-month-old wild-type group, no such increment was observed in age-matched 3xTg-AD, whereas the amount of Arc+ cells in CA1 increased in both groups. Further, we detected that CA3 neurons with amyloid-β were much more likely to express Arc protein under basal conditions. We propose that in 3xTg-AD mice, intraneuronal amyloid-β expression in CA3 could increase unspecific neuronal activation and subsequent Arc protein expression, which might impair further memory-stabilizing processes.

%B J Alzheimers Dis %V 51 %P 69-79 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26836189?dopt=Abstract %R 10.3233/JAD-150975 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Tobacco Smoke-Induced Brain White Matter Myelin Dysfunction: Potential Co-Factor Role of Smoking in Neurodegeneration. %A Yu, Rosa %A Deochand, Chetram %A Krotow, Alexander %A Leão, Raiane %A Tong, Ming %A Agarwal, Amit R %A Cadenas, Enrique %A de la Monte, Suzanne M %K 2',3'-Cyclic-Nucleotide Phosphodiesterases %K AC133 Antigen %K Animals %K Antigens, CD %K Brain %K Disease Models, Animal %K Galactosylceramides %K Gene Expression Regulation %K Glycoproteins %K Leukoencephalopathies %K Male %K Mice %K Nerve Degeneration %K Nerve Tissue Proteins %K Neuroglia %K Neurons %K Oligodendroglia %K Papain %K Peptides %K Smoking %K Tobacco %K Transcription Factors %X

BACKGROUND: Meta-analysis studies showed that smokers have increased risk for developing Alzheimer's disease (AD) compared with non-smokers, and neuroimaging studies revealed that smoking damages white matter structural integrity.

OBJECTIVE: The present study characterizes the effects of side-stream (second hand) cigarette smoke (CS) exposures on the expression of genes that regulate oligodendrocyte myelin-synthesis, maturation, and maintenance and neuroglial functions.

METHODS: Adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). The frontal lobes were used for histology and qRT-PCR analysis.

RESULTS: Luxol fast blue, Hematoxylin and Eosin stained histological sections revealed CS-associated reductions in myelin staining intensity and narrowing of the corpus callosum. CS exposures broadly decreased mRNA levels of immature and mature oligodendrocyte myelin-associated, neuroglial, and oligodendrocyte-related transcription factors. These effects were more prominent in the CS8 compared with CS4 group, suggesting that molecular abnormalities linked to white matter atrophy and myelin loss worsen with duration of CS exposure. Recovery normalized or upregulated less than 25% of the suppressed genes; in most cases, inhibition of gene expression was either sustained or exacerbated.

CONCLUSION: CS exposures broadly inhibit expression of genes needed for myelin synthesis and maintenance. These adverse effects often were not reversed by short-term CS withdrawal. The results support the hypothesis that smoking contributes to white matter degeneration, and therefore could be a key risk factor for a number of neurodegenerative diseases, including AD.

%B J Alzheimers Dis %V 50 %P 133-48 %8 2016 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639972?dopt=Abstract %R 10.3233/JAD-150751 %0 Journal Article %J Nature %D 2014 %T REST and stress resistance in ageing and Alzheimer's disease. %A Lu, Tao %A Aron, Liviu %A Zullo, Joseph %A Pan, Ying %A Kim, Haeyoung %A Chen, Yiwen %A Yang, Tun-Hsiang %A Kim, Hyun-Min %A Drake, Derek %A Liu, X Shirley %A Bennett, David A %A Colaiácovo, Monica P %A Yankner, Bruce A %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Autophagy %K Brain %K Caenorhabditis elegans Proteins %K Cell Death %K Cell Nucleus %K Chromatin Immunoprecipitation %K Cognition %K DNA-Binding Proteins %K Down-Regulation %K Frontotemporal Dementia %K Gene Expression Regulation %K Humans %K Lewy Body Disease %K Longevity %K Mice %K Mild Cognitive Impairment %K Neurons %K Neuroprotective Agents %K Oxidative Stress %K Phagosomes %K Repressor Proteins %K Transcription Factors %K Up-Regulation %K Wnt Signaling Pathway %K Young Adult %X

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer's disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer's disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer's disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

%B Nature %V 507 %P 448-54 %8 2014 Mar 27 %G eng %N 7493 %1 http://www.ncbi.nlm.nih.gov/pubmed/24670762?dopt=Abstract %R 10.1038/nature13163 %0 Journal Article %J Nature %D 2012 %T An epigenetic blockade of cognitive functions in the neurodegenerating brain. %A Gräff, Johannes %A Rei, Damien %A Guan, Ji-Song %A Wang, Wen-Yuan %A Seo, Jinsoo %A Hennig, Krista M %A Nieland, Thomas J F %A Fass, Daniel M %A Kao, Patricia F %A Kahn, Martin %A Su, Susan C %A Samiei, Alireza %A Joseph, Nadine %A Haggarty, Stephen J %A Delalle, Ivana %A Tsai, Li-Huei %K Acetylation %K Alzheimer Disease %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Epigenesis, Genetic %K Gene Expression Regulation %K Gene Knockdown Techniques %K Hippocampus %K Histone Deacetylase 2 %K Histones %K Humans %K Hydrogen Peroxide %K Memory Disorders %K Mice %K Neurodegenerative Diseases %K Neuronal Plasticity %K Peptide Fragments %K Phosphorylation %K Promoter Regions, Genetic %K Receptors, Glucocorticoid %K RNA Polymerase II %X

Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.

%B Nature %V 483 %P 222-6 %8 2012 Mar 8 %G eng %N 7388 %1 http://www.ncbi.nlm.nih.gov/pubmed/22388814?dopt=Abstract %R 10.1038/nature10849 %0 Journal Article %J Neuron %D 2012 %T Propagation of tau pathology in a model of early Alzheimer's disease. %A de Calignon, Alix %A Polydoro, Manuela %A Suárez-Calvet, Marc %A William, Christopher %A Adamowicz, David H %A Kopeikina, Kathy J %A Pitstick, Rose %A Sahara, Naruhiko %A Ashe, Karen H %A Carlson, George A %A Spires-Jones, Tara L %A Hyman, Bradley T %K Age Factors %K Alzheimer Disease %K Animals %K Disease Models, Animal %K Disease Progression %K Entorhinal Cortex %K Epitopes %K Gene Expression Regulation %K Glial Fibrillary Acidic Protein %K Gliosis %K Hippocampus %K Humans %K Mice %K Mice, Inbred C57BL %K Mice, Transgenic %K Mutation %K Nerve Degeneration %K Neurofibrillary Tangles %K Neurons %K RNA, Messenger %K Serine %K tau Proteins %K Tauopathies %X

Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimer's disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.

%B Neuron %V 73 %P 685-97 %8 2012 Feb 23 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22365544?dopt=Abstract %R 10.1016/j.neuron.2011.11.033