Mitochondiral enzymes/oxidative stress in Alzheimer's

描述（改编自应用程序）：大脑代谢减少， 氧化应激是AD的特征性特征。的机制 这些变化的定义尚不明确。最近的研究表明， 线粒体损伤的标志物，α-酮戊二酸脱氢酶复合物 （KGDHC）与临床残疾的相关性至少与斑块和 纠结也算已知KGDHC和其他几种线粒体酶是 对活性氧（ROS）敏感。本提案中的研究将 测试假设，损伤或选择线粒体酶的活性氧是 一个重要组成部分的级联或事件，导致减少 代谢和AD中的认知缺陷。这一假设将得到检验 研究人员合作者在Mt. 西奈（纽约）ADRC，他们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 使用临床痴呆评级（CDR）。氧化应激的定量标志物 将比较特定线粒体酶的应激和活性， 临床状态（CDR）和AD病理学的标志物，包括斑块和 缠结计数，通过改进的统计方法中所述的建议。 并利用组织培养模型进行机理实验 特定活性氧对同一线粒体活性的影响 在人类尸体解剖的必要相关研究中检查的酶 个脑袋本实验采用的模型为：（1）培养AD患者的成纤维细胞， ROS对具有相同遗传背景的细胞的影响， （2）神经元的培养模型， 易受攻击的细胞类型这些模型还将提供系统， 测试限制或扭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.