氧化应激诱导的线粒体变化及钙动力学在阿尔茨海默病病理生理学中的作用

Oxidant-induced changes in mitochondria and calcium dynamics in the pathophysiology of Alzheimer's disease.

作者信息

Gibson Gary E, Karuppagounder Saravanan S, Shi Qingli

机构信息

Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, White Plains, NY 10605, USA.

出版信息

Ann N Y Acad Sci. 2008 Dec;1147:221-32. doi: 10.1196/annals.1427.038.

Considerable data support the hypothesis that mitochondrial abnormalities link gene defects and/or environmental insults to the neurodegenerative process. The interaction of oxidants with calcium and the mitochondrial enzymes of the tricarboxylic acid cycle are central to that relationship. Abnormalities that were discovered in brains or fibroblasts from patients with Alzheimer's disease (AD) have been modeled in vitro and in vivo to assess their pathophysiological importance and to determine how they might be reversed. The conclusions are consistent with the hypothesis that the AD-related abnormalities result from oxidative stress. The selection of compounds for reversal is complex because the actions of the relevant compounds vary under different conditions, such as cell redox states and acute versus chronic changes. However, the models that have been developed are useful for testing the effectiveness of the potential medications. The results suggest that the reversal of mitochondrial deficits and a reduction in oxidative stress will reduce clinical and pathological changes and benefit patients.

大量数据支持这样一种假说，即线粒体异常将基因缺陷和/或环境损伤与神经退行性过程联系起来。氧化剂与钙以及三羧酸循环的线粒体酶之间的相互作用是这种关系的核心。在阿尔茨海默病（AD）患者的大脑或成纤维细胞中发现的异常已在体外和体内进行建模，以评估其病理生理重要性，并确定如何逆转这些异常。这些结论与AD相关异常是由氧化应激导致的假说一致。用于逆转的化合物的选择很复杂，因为相关化合物的作用在不同条件下会有所不同，例如细胞氧化还原状态以及急性与慢性变化。然而，已开发的模型对于测试潜在药物的有效性很有用。结果表明，线粒体缺陷的逆转和氧化应激的减轻将减少临床和病理变化，并使患者受益。