دانلود مقاله ISI انگلیسی شماره 30765
عنوان فارسی مقاله

آسیب شناسی بیماری آلزایمر در سالمندان سالم شناختی: مطالعه ژنوم

کد مقاله سال انتشار مقاله انگلیسی ترجمه فارسی تعداد کلمات
30765 2011 10 صفحه PDF سفارش دهید محاسبه نشده
خرید مقاله
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عنوان انگلیسی
Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study
منبع

Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)

Journal : Neurobiology of Aging, Volume 32, Issue 12, December 2011, Pages 2113–2122

کلمات کلیدی
ژنوم مطالعه ارتباط - بیماری آلزایمر - بدون دمانس سالمندان مبتلا به نوروپاتولوژی - بدون دمانس سالمندان بدون نوروپاتولوژی -
پیش نمایش مقاله
پیش نمایش مقاله آسیب شناسی بیماری آلزایمر در سالمندان سالم شناختی: مطالعه ژنوم

چکیده انگلیسی

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through β-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.

مقدمه انگلیسی

Prevalence rates for Alzheimer disease (AD) climb steadily from ∼1% in 65-year-olds to as high as 40% by the age of 85 (Hebert et al., 2003). Despite these dire figures, some elderly individuals remain dementia-free throughout their life and, of these, a proportion exhibit substantial AD neuropathology, in the form of amyloid plaques and neurofibrillary tangles (NFTs), at autopsy (Erten-Lyons et al., 2009 and Bennett et al., 2005). Thus, individuals differ in their capacity to maintain normative cognitive function even within the context of neuropathological structural changes associated with AD. There are a number of ways in which genetic mechanisms might promote cognitive health. On one hand, genetic variants may prevent development of the neuropathological substrate that underlies susceptibility to cognitive dysfunction. Alternatively, in the presence of neuropathology, genetic variants may mitigate the effects of AD-related lesions that otherwise result in cognitive decline. The first case provides greater guarantee of cognitive health. Thus, it is important to identify genetic variants associated with development of AD neuropathology within the context of cognitive resilience. We conducted a genome-wide SNP association study (GWAS) to identify genetic mechanisms involved in healthy brain aging. This study was based on a sample of non-demented, deceased subjects with autopsy who were members of longitudinal healthy aging cohorts at 10 NIA-funded Alzheimer Disease Centers (ADC). These subjects comprised one group with little or no evidence of NFT formation, and one with substantial or severe levels of NFT formation in critical brain regions. We report results that implicate variants in the glycoprotein reelin (RELN) as key elements in the molecular basis of AD-related neuropathological processes. We provide additional support for these statistical findings with immunohistochemical data for reelin expression in AD-related brain regions in a subset of our study subjects. To our knowledge, this is the first GWAS that specifically addresses genetic mechanisms of AD neuropathology in non-demented elderly with post-mortem examinations.

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