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https://www.readbyqxmd.com/read/28444230/apoe-%C3%AE%C2%B54-%C3%AE%C2%B54-diminishes-neurotrophic-function-of-human-ipsc-derived-astrocytes
#1
Jing Zhao, Mary D Davis, Yuka Atagi, Mitsuru Shinohara, Neill R Graff-Radford, Steven G Younkin, Zbigniew K Wszolek, Takahisa Kanekiyo, Guojun Bu
The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have distinct gene expression profile compare with rodent astrocytes...
April 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28435985/elucidating-the-a%C3%AE-42-anti-aggregation-mechanism-of-action-of-tramiprosate-in-alzheimer-s-disease-integrating-molecular-analytical-methods-pharmacokinetic-and-clinical-data
#2
Petr Kocis, Martin Tolar, Jeremy Yu, William Sinko, Soumya Ray, Kaj Blennow, Howard Fillit, John A Hey
BACKGROUND: Amyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer's disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease...
April 24, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28434655/apolipoprotein-e-receptors-and-modulation-of-alzheimer-s-disease
#3
REVIEW
Na Zhao, Chia-Chen Liu, Wenhui Qiao, Guojun Bu
Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation...
March 14, 2017: Biological Psychiatry
https://www.readbyqxmd.com/read/28413778/family-history-and-apoe4-risk-for-alzheimer-s-disease-impact-the-neural-correlates-of-episodic-memory-by-early-midlife
#4
M N Rajah, L M K Wallace, E Ankudowich, E H Yu, A Swierkot, R Patel, M M Chakravarty, D Naumova, J Pruessner, R Joober, S Gauthier, S Pasvanis
Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58 yrs) with a family history of late onset AD (MA+ FH), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA+ FH + APOE4), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH - APOE4 MA controls...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28399184/genetic-factors-influencing-frontostriatal-dysfunction-and-the-development-of-dementia-in-parkinson-s-disease
#5
Ismael Huertas, Silvia Jesús, Francisco Javier García-Gómez, José Antonio Lojo, Inmaculada Bernal-Bernal, Marta Bonilla-Toribio, Juan Francisco Martín-Rodriguez, David García-Solís, Pilar Gómez-Garre, Pablo Mir
The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study's objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients...
2017: PloS One
https://www.readbyqxmd.com/read/28389477/efad-transgenic-mice-as-a-human-apoe-relevant-preclinical-model-of-alzheimer-s-disease
#6
Leon M Tai, Deebika Balu, Evangelina Avila-Munoz, Laila Abdullah, Riya Thomas, Nicole Collins, Ana Carolina Valencia-Olvera, Mary Jo LaDu
Identified in 1993, APOE4 is the greatest genetic risk factor for sporadic Alzheimers disease (AD), increasing risk up to 12-fold compared to APOE3, with APOE2 decreasing AD risk. However, the functional effects of APOE4 on AD pathology remain unclear and, in some cases, controversial. In vivo progress to understand how the human (h)-APOE genotypes effect AD pathology has been limited by the lack of a tractable familial AD-transgenic (FAD-Tg) mouse model expressing h- rather than mouse (m)-APOE. The disparity between m- and h-apoE is relevant for virtually every AD-relevant pathway, including amyloid beta deposition and clearance, neuroinflammation, tau pathology, neural plasticity and cerebrovascular deficits...
April 7, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28383643/observational-cohort-study-examining-apolipoprotein-e-status-and-preoperative-neuropsychological-performance-as-predictors-of-post-operative-delirium-in-an-older-elective-arthroplasty-population
#7
Emma Louise Cunningham, Tim Mawhinney, David Beverland, Seamus O'Brien, Daniel F McAuley, Rebecca Cairns, Peter Passmore, Bernadette McGuinness
Introduction: delirium following surgery is common and is associated with negative outcomes. Preoperative cognitive impairment has been shown to be a risk factor for post-operative delirium. Often the cognitive tests used are cumbersome. This study tests the hypothesis that the quantification of brain vulnerability, using Apolipoprotein E (ApoE) status and neuropsychological tests, both traditional and more easily administered, can quantify the risk of post-operative delirium following elective primary arthroplasty surgery...
April 5, 2017: Age and Ageing
https://www.readbyqxmd.com/read/28381516/randomized-controlled-trials-in-mild-cognitive-impairment-sources-of-variability
#8
Ronald C Petersen, Ronald G Thomas, Paul S Aisen, Richard C Mohs, Maria C Carrillo, Marilyn S Albert
OBJECTIVE: To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI). METHODS: Placebo group data were obtained from 2 National Institute on Aging (NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil...
April 5, 2017: Neurology
https://www.readbyqxmd.com/read/28372324/apolipoprotein-e-isoforms-differentially-regulate-alzheimer-s-disease-and-amyloid-%C3%AE-induced-inflammatory-response-in-vivo-and-in-vitro
#9
Evan Dorey, Michelle Bamji-Mirza, Dema Najem, Yan Li, Hong Liu, Debbie Callaghan, Douglas Walker, Lih-Fen Lue, Danica Stanimirovic, Wandong Zhang
Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer's disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42. Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3...
2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28366823/redox-status-of-serum-apolipoprotein-e-and-its-impact-on-hdl-cholesterol-levels
#10
Kazuyoshi Yamauchi, Yuka Ebihara, Yasushi Kawakami
BACKGROUND: Apolipoprotein E (apoE) is closely involved in the pathogenesis of apoE-related diseases, such as Alzheimer's disease and cardiovascular disease. The redox modulation of cysteine-thiols in a protein is involved in various pathophysiological regulations; however, that of apoE has not been studied in detail. Herein, we devised an analytical method to determine the redox status of serum apoE and assessed its relation to serum cholesterol levels and apoE phenotype. METHODS: The present method was based on a band shift assay, using a photocleavable maleimide-conjugated polyethylene glycol...
March 30, 2017: Clinical Biochemistry
https://www.readbyqxmd.com/read/28356228/co-injection-of-a%C3%AE-1-40-and-apoe4-impaired-spatial-memory-and-hippocampal-long-term-potentiation-in-rats
#11
Meina Wu, Yexin He, Jun Zhang, Junting Yang, Jinshun Qi
Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimer's disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Aβ)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Aβ1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Aβ1-40 and ApoE4, and investigated the effects of co-application of Aβ1-40 and ApoE4 on cognitive behavior and synaptic plasticity...
March 27, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28341646/cardiorespiratory-fitness-alters-the-influence-of-a-polygenic-risk-score-on-biomarkers-of-ad
#12
Stephanie A Schultz, Elizabeth A Boots, Burcu F Darst, Henrik Zetterberg, Kaj Blennow, Dorothy F Edwards, Rebecca L Koscik, Cynthia M Carlsson, Catherine L Gallagher, Barbara B Bendlin, Sanjay Asthana, Mark A Sager, Kirk J Hogan, Bruce P Hermann, Dane B Cook, Sterling C Johnson, Corinne D Engelman, Ozioma C Okonkwo
OBJECTIVE: To examine whether a polygenic risk score (PRS) derived from APOE4, CLU, and ABCA7 is associated with CSF biomarkers of Alzheimer disease (AD) pathology and whether higher cardiorespiratory fitness (CRF) modifies the association between the PRS and CSF biomarkers. METHODS: Ninety-five individuals from the Wisconsin Registry for Alzheimer's Prevention were included in these cross-sectional analyses. They were genotyped for APOE4, CLU, and ABCA7, from which a PRS was calculated for each participant...
March 24, 2017: Neurology
https://www.readbyqxmd.com/read/28337631/upregulation-of-mineralocorticoid-receptor-in-the-hypothalamus-associated-with-a-high-anxiety-like-level-in-apolipoprotein-e4-transgenic-mice
#13
Fan-Tao Meng, Jun Zhao, Hui Fang, Li-Feng Zhang, Hui-Mei Wu, Ya-Jing Liu
Anxiety symptoms occur in a large portion of Alzheimer's disease (AD) patients. ApolipoproteinE-4 (ApoE ε4 allele), a risk factor for AD, has been recognized as an important contributor to psychiatric disorders. In the present study, we aimed to investigate the corticosterone level in relation to anxiety-like behavior changes in transgenic male mice with different glial fibrillary acidic protein (GFAP)-ApoE isoforms. GFAP-ApoE4 transgenic mice aged 3 months showed higher anxiety-like behavior in open field, light-dark box and elevated plus maze tasks compared with that of age-matched GFAP-ApoE3 mice...
March 24, 2017: Behavior Genetics
https://www.readbyqxmd.com/read/28335828/dha-brain-uptake-and-apoe4-status-a-pet-study-with-1-11-c-dha
#14
Hussein N Yassine, Etienne Croteau, Varun Rawat, Joseph R Hibbeln, Stanley I Rapoport, Stephen C Cunnane, John C Umhau
BACKGROUND: The apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer's disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes. METHODS: Using positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-(11)C]-DHA (J in), and regional cerebral blood flow using [(15)O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19-65 years)...
March 23, 2017: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/28321820/apolipoprotein-e4-suppresses-neuronal-specific-gene-expression-in-maturing-neuronal-progenitor-cells-exposed-to-hiv
#15
Rebeca Geffin, Ricardo Martinez, Alicia de Las Pozas, Biju Issac, Micheline McCarthy
The apolipoprotein ε4 gene allele and the apolipoprotein E4 protein (ApoE4) are important host susceptibility factors linked to neurocognitive disorders associated with HIV infection or Alzheimer's disease. Our previous studies showed differential effects of the two most common human ApoE genotypes, APOE3/3 and APOE3/4, on gene expression by differentiating human neuroepithelial progenitor cells continuously exposed to HIV. To investigate the effects of ApoE3 versus ApoE4 isoforms specifically on maturing neurons, we adapted a human neuronal progenitor cell line, hNP1, with ApoE genotype APOE3/3...
March 20, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28299413/apolipoprotein-e-the-resilience-gene
#16
Lisa M James, Brian E Engdahl, Apostolos P Georgopoulos
The apolipoprotein E (apoE) gene has been implicated in various conditions, most notably Alzheimer's disease and coronary artery disease. A predisposing role of the apoE4 isoform and a protective role of apoE2 isoform in those diseases have been documented. Here we investigated the role of apoE in resilience to trauma. Three hundred and forty-three US veterans were genotyped for apoE and were assessed for their lifetime trauma exposure (trauma score, T) and severity of posttraumatic stress disorder symptoms (PCL)...
March 15, 2017: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
https://www.readbyqxmd.com/read/28298911/autoantibodies-against-the-n-methyl-d-aspartate-receptor-subunit-nr1-untangling-apparent-inconsistencies-for-clinical-practice
#17
REVIEW
Hannelore Ehrenreich
This viewpoint review provides an integrative picture of seemingly contradictory work published on N-methyl-d-aspartate receptor 1 (NMDAR1) autoantibodies (AB). Based on the present state of knowledge, it gives recommendations for the clinical decision process regarding immunosuppressive treatment. Brain antigen-directed AB in general and NMDAR1-AB in particular belong to a preexisting autoimmune repertoire of mammals including humans. Specific autoimmune reactive B cells may get repeatedly (perhaps transiently) boosted by various potential stimulants (e...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28298292/cellular-cholesterol-homeostasis-in-alzheimer-s-disease
#18
Ta Yuan Chang, Yoshio Yamauchi, Mazahir Hasan, Catherine Cy Chang
Alzheimer's disease [AD] is the most common form of dementia in older adults. Currently, there is no cure for AD. The hallmark of AD is the accumulation of extracellular amyloid plaques composed of amyloid beta peptides [Abeta; especially Abeta1-42], and neurofibrillary tangles, composed of hyper-phosphorylated tau, accompanied with chronic neuroinflammation. Abeta are derived from the amyloid precursor protein APP. The oligomeric form of Abeta is probably the most neurotoxic species; its accumulation eventually forms the insoluble and aggregated amyloid plaques...
March 15, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28292942/the-apoe-receptors-vldlr-and-apoer2-in-central-nervous-system-function-and-disease
#19
Courtney Lane-Donovan, Joachim Herz
The low-density lipoprotein receptor (LDLR) family has long been studied for its role in cholesterol transport and metabolism; however, the identification of apolipoprotein E4 (ApoE4), an LDLR ligand, as a genetic risk factor for late-onset Alzheimers disease (AD) has focused attention on the role this receptor family plays in the central nervous system (CNS). Surprisingly, it was discovered that two LDLR family members, Apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor (Vldlr), play key roles in brain development and adult synaptic plasticity, primarily by mediating Reelin signaling...
March 14, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28276521/a-randomized-trial-and-novel-spr-technique-identifies-altered-lipoprotein-ldl-receptor-binding-as-a-mechanism-underlying-elevated-ldl-cholesterol-in-apoe4s
#20
M V Calabuig-Navarro, K G Jackson, C F Kemp, D S Leake, C M Walden, J A Lovegrove, A M Minihane
At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status...
March 9, 2017: Scientific Reports
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