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AD Risk (ad + risk)

Distribution by Scientific Domains
Life Sciences60%

Selected Abstracts

Estradiol enhances long term potentiation in hippocampal slices from aged apoE4-TR mice

HIPPOCAMPUS, Issue 12 2007
Sung Hwan Yun
Abstract Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24,27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy. © 2007 Wiley-Liss, Inc. [source]

A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease

AGING CELL, Issue 2 2009
Marķa Recuero
Summary Oxidative stress, which plays a critical role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), is intimately linked to aging , the best established risk factor for AD. Studies in neuronal cells subjected to oxidative stress, mimicking the situation in AD brains, are therefore of great interest. This paper reports that, in human neuronal cells, oxidative stress induced by the free radical-generating xanthine/xanthine oxidase (X-XOD) system leads to apoptotic cell death. Microarray analyses showed a potent activation of the cholesterol biosynthesis pathway following reductions in the cell cholesterol synthesis caused by the X-XOD treatment; furthermore, the apoptosis was reduced by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) expression with an interfering RNA. The potential importance of this mechanism in AD was investigated by genetic association, and it was found that HMGCR, a key gene in cholesterol metabolism and among those most strongly upregulated, was associated with AD risk. In summary, this work presents a human cell model prepared to mimic the effect of oxidative stress in neurons that might be useful in clarifying the mechanism involved in free radical-induced neurodegeneration. Gene expression analysis followed by genetic association studies indicates a possible link among oxidative stress, cholesterol metabolism and AD. [source]

Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study

AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 5 2002
G. Roks
Abstract The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this ,491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the ,491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the ,491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the ,491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk. © 2002 Wiley-Liss, Inc. [source]

The combinations of TNF,,308 and IL-6 ,174 or IL-10 ,1082 genes polymorphisms suggest an association with susceptibility to sporadic late-onset Alzheimer's disease

ACTA NEUROLOGICA SCANDINAVICA, Issue 6 2009
P. Vural
Objective,,, Single nucleotide polymorphisms in the regulatory regions of the cytokine genes for tumor necrosis factor , (TNF,), interleukin (IL)-6 and IL-10 have been suggested to influence the risk of Alzheimer's disease (AD) with conflicting results. Aim,,, To investigate the TNF,,308, IL-6 ,174 and IL-10 ,1082 gene polymorphisms as susceptibility factors for AD. Methods,,, We analyzed genotype and allele distributions of these polymorphisms in 101 sporadic AD patients and 138 healthy controls. Results,,, Heterozygotes (AG) or combined genotype (AG+AA) for IL-10 ,1082 were associated with approximately two-fold increase in the risk of AD. Carriers of A alleles of both TNF,,308 and IL-10 ,1082 had 6.5 times higher risk for AD in comparison with non-carriers. Concomitant presence of both mutant TNF,,308 A and IL-6 ,174 C alleles raised three-fold the AD risk, whereas there was no notable risk for AD afflicted by IL-6 ,174 polymorphism alone. Conclusion,,, Our results suggest that TNF, and IL-10 promoter polymorphism might be a risk factor for AD. The combined effects of TNF,,308, IL-6 ,174 and IL-10 ,1082 variant alleles may be more decisive to induce functional differences and modify the risk for AD. [source]

Epistasis between tau phosphorylation regulating genes (CDK5R1 and GSK-3,) and Alzheimer's disease risk

ACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009
I. Mateo
Objective,,, Glycogen synthase kinase-3, (GSK-3,) and cyclin-dependent kinase 5 (CDK5) have been implicated as two major protein kinases involved in the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain, and the development of neurofibrillary tangles. CDK5 regulatory subunit 1 (CDK5R1) encodes for p35, a protein required for activation of CDK5. As both CDK5R1 and GSK-3, genes are related to phosphorylation of tau, we examined the combined contribution of these genes to the susceptibility for AD. Methods,,, In a case,control study in 283 AD patients and 263 healthy controls, we examined the combined effects between CDK5R1 (3,-UTR, rs735555) and GSK-3, (,50, rs334558) polymorphisms on susceptibility to AD. Results,,, Subjects carrying both the CDK5R1 (3,-UTR, rs735555) AA genotype and the GSK-3, (,50, rs334558) CC genotype had a 12.5-fold decrease in AD risk (adjusted by age, sex and APOE status OR = 0.08, 95% CI = 0.01,0.76, P = 0.03), suggesting synergistic effects (epistasis) between both genes. Conclusion,,, These data support a role for tau phosphorylation regulating genes in risk for AD. [source]