Mitochondiral enzymes/oxidative stress in Alzheimer's

描述(改编自应用程序)：大脑新陈代谢减弱和 氧化应激是阿尔茨海默病的特征。潜在的机制 到目前为止，这些变化的定义还不够明确。最近的研究表明， 线粒体损伤的标志--cc-酮戊二酸脱氢酶复合体 (KGDHC)，与临床残疾的相关性至少与斑块和 纠缠也算数。KGDHC和其他几种线粒体酶是已知的 对活性氧(ROS)敏感。这项建议中的研究将 验证ROS损伤或选择线粒体酶的假设是 连锁反应或事件中的一个重要组成部分，会导致 与AD的新陈代谢和认知缺陷有关。这一假设将得到检验。 关于调查人员合作者在山上收集的人类尸检脑 西奈(纽约)ADRC，他们从纽约收集了数百个大脑样本 已确定临终前神经心理状态的患者 采用临床痴呆评定量表(CDR)。氧化的定量标记物 应激和特定线粒体酶的活性将与 临床状态(CDR)和AD病理标志物，包括斑块和 纠缠计数，通过提案中描述的改进的统计方法。 还将使用组织培养模型来进行机械实验 特定ROS对同一线粒体活性的影响 人体尸检的必要相关性研究中的酶检测 大脑。模型将为：(1)培养AD患者成纤维细胞，以检测 ROS对遗传背景相同的细胞的影响 疾病的表达；(2)神经元的培养模型 阿尔茨海默病大脑中易受攻击的细胞类型。这些型号还将提供以下系统 测试限制或逆转变化的方法的有效性 线粒体。

DESCRIPTION (Adapted from the application): Diminished brain metabolism and oxidative stress are characteristic features of AD. The mechanisms underlying these changes are as yet poorly defined. The recent studies indicate that a marker of mitochondrial damage, the cc-ketoglutarate dehydrogenase complex (KGDHC), correlates at least as well with clinical disability as do plaque and tangle counts. KGDHC and several other mitochondrial enzymes are known to be sensitive to reactive oxygen species (ROS). The studies in this proposal will test the hypothesis that impairment or select mitochondrial enzymes by ROS is an important component of the cascade or events that leads to diminished metabolism and to the cognitive deficits in AD. This hypothesis will be tested on human autopsy brains collected by the investigators collaborators at the Mt Sinai (NY) ADRC, who have collected several hundred samples of brain from patients whose pre-terminal neuropsychological status has been determined using the Clinical Dementia Rating (CDR). Quantitative markers of oxidative stress and activities of specific mitochondrial enzymes will be compared to clinical status (CDR) and to markers of AD pathology including plaque and tangle counts, by refined statistical methods described in the proposal. Tissue culture models will also be used, so as to do mechanistic experiments on the effects of specific ROS on the activities of the same mitochondrial enzymes examined in the necessarily correlational studies of human autopsied brain. The models will be: (1) cultured fibroblasts from AD patients, to test the effects of ROS on cells which have the same genetic background as that in which the disease is expressed; (2) culture models of neurons, the most vulnerable cell type in AD brains. These models will also provide systems to test the efficacy of approaches to limit or reverse the changes in mitochondria.