Mitochondrial dysfunction and Alzheimer's disease
Mitochondrial dysfunction and Alzheimer's disease
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DOI：
10.2174/156720506779025215
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发表时间：
2006-12-01
影响因子：
2.1
通讯作者：
Yan, Shi Du
中科院分区：
文献类型：
--
作者：
Chen, Xi;Stern, David;Yan, Shi Du
线粒体功能障碍与阿尔茨海默病（AD）的代谢异常有关。对与阿尔茨海默病易感性相关的线粒体DNA变异的研究产生了相互矛盾的结果。年龄相关的体细胞线粒体DNA缺失积累已被认为在AD的发展中起致病作用。最近的研究表明，淀粉样蛋白- β肽（A β）在线粒体基质中逐渐积累，正如在过表达突变淀粉样蛋白前体蛋白（APP）的转基因小鼠和AD患者尸检大脑中所证明的那样。在AD患者和AD型转基因小鼠模型中，β介导的线粒体应激可通过大脑耗氧量受损和呼吸链复合物III和IV活性降低得到证实。此外，我们的研究表明，在转基因ad型小鼠模型中，线粒体内A β与线粒体酶淀粉样蛋白结合醇脱氢酶（ABAD）的相互作用抑制了其酶活性，增强了活性氧（ROS）的产生，损害了能量代谢，并加剧了A β诱导的空间学习/记忆缺陷和神经病理变化。阻断ABAD-A - β相互作用可能是阿尔茨海默病的潜在治疗策略。
Mitochondrial dysfunction has been implicated in causing metabolic abnormalities in Alzheimer's disease (AD). The searches for mitochondrial DNA variants associated with AD susceptibility have generated conflicting results. The age-related accumulation of somatic mitochondrial DNA deletion has been suggested to play a pathogenic role in the development of AD. Recent studies have demonstrated that amyloid-beta peptide (A beta) progressively accumulates in mitochndrial matrix, as demonstrated in both transgenic mice over-expressing mutant amyloid precursor protein (APP) and autopsy brain from AD patients. A beta-mediated mitochondrial stress was evidenced by impaired oxygen consumption and decreased respiratory chain complexes III and IV activities in brains from AD patients and AD-type transgenic mouse model. Furthermore, our studies indicated that interaction of intramitochondrial A beta with a mitochondrial enzyme, amyloid binding alcohol dehydrogenase (ABAD), inhibits its enzyme activity, enhances generation of reactive oxygen species (ROS), impairs energy metabolism, and exaggerates A beta-induced spatial learning/memory deficits and neuropathological changes in transgenic AD-type mouse model. Interception of ABAD-A beta interaction may be a potential therapeutic strategy for Alzheimer's disease.