Brain Aging & Gene Expression Patterns Using Microarrays

描述（由申请人提供）：本项目使用微阵列技术收集了一组独特的脑标本，以测试关于正常衰老和阿尔茨海默病（AD）发病机制中炎症与突触退化和神经元死亡之间关系的假设。由于AD风险是由衰老驱动的，我们将评估整个成年期的正常大脑，以确定基因表达的衰老变化，这可能会引发前馈级联反应，导致不可逆的神经退行性变。为了实施该项目，已经组建了一个由代表6个ADC的神经科学家、神经病理学家和临床医生组成的联盟。内嗅皮层/下托（EC）、海马（HPC）、上级额回（SFG）和感觉运动皮层（SMC）的冷冻、未固定块（250 mg/样本）将主要从5个完善的NIA ADC脑库中获得。组织块将来自神经病理学正常对照、MCI、早期轻度-中度AD和晚期中度-重度AD（N=10/组）。患有痴呆但无显著AD病理学的PD病例（N=10/组）将作为疾病对照。病例分组将基于常见的ADC生前临床标准和死后神经病理学标准，特别是Braak分期。实验组将在性别和死后间隔方面进行匹配，其中没有一个将超过6小时，在此期间，我们的初步研究表明RNA降解相对较少。将表征总RNA的大小分布，并通过Affyssin基因阵列进行分析。数据将存储在专用硬盘中，并搜索可能是AD研究的早期标志物和根本原因的特定途径的变化。本建议将侧重于两个假设：1）。在衰老和轻度病理过程中，选择与突触功能相关的基因在认知衰退的初始阶段显示出补偿性变化，并且这些变化随着退化的发展而下降。2）。脑炎症是导致转化为MCI和/或AD的关键触发机制，并且炎症反应在突触变化之后或之前。一旦最初的主要论文发表，所有的数据将通过NACC提供给各个研究人员，以分析测试他们自己的假设。

DESCRIPTION (provided by applicant): This project assembles a unique set of brain specimens to test hypotheses on the relationship of inflammation to synaptic regression and neuron death during normal aging and Alzheimer disease (AD) pathogenesis using microarray technology. Because AD risk is driven by aging, we will evaluate normal brains across the adult life span to identify aging changes in gene expression, which may trigger feedforward cascades leading to irreversible neurodegeneration. To carry out this project a consortium of neuroscientists, neuropathologists and clinicians representing 6 ADCs has been assembled. Frozen, unfixed blocks (250 mg/sample) of the entorhinal cortex/subiculum (EC), hippocampus (HPC), superior frontal gyrus (SFG), and sensory-motor cortex (SMC) will be obtained primarily from five well-established NIA ADC brain banks. The tissue blocks will derive from neuropathologically normal controls, MCI, early mild-moderate AD, and terminal moderate-severe AD (N=10/group). PD cases with dementia but without significant AD pathology (N=10/group) will serve as a disease control. Assignment of cases to groups will be based on common ADC antemortem clinical criteria and postmortem neuropathologic criteria, particularly Braak staging. The experimental groups will be matched for gender and postmortem intervals, none of which will exceed 6 hours, a period during which our preliminary studies suggest that relatively little RNA degradation occurs. Total RNA will be characterized for size distribution and analyzed by Affymetrix gene arrays. Data will be stored in a dedicated hard-drive and searched for changes in specific pathways that may be early markers for and underlying causes of AD study. This proposal will focus on two hypotheses: 1). During aging and mild pathology select genes linked to synaptic function show compensatory changes in the initial stages of cognitive decline and these decline as degeneration evolves. 2). Brain inflammation is a key triggering mechanism resulting in conversion to MCI and/or AD and that inflammatory responses follow or precede synaptic change. Once an initial primary paper is published the overall data will be made available to the field via NACC for various investigators to analyze for the testing their own hypotheses.