Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
J Alzheimers Dis. 2010;20 Suppl 2:S569-78. doi: 10.3233/JAD-2010-100357.
Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Abnormalities in mitochondrial properties include impaired energy metabolism, defects in key respiratory enzyme activity/function, accumulation/generation of mitochondrial reactive oxygen species, and formation of membrane permeability transition pore. While the mechanisms underlying mitochondrial dysfunction remain incompletely understood, recent studies provide substantial evidence for the progressive accumulation of mitochondrial Abeta, which directly links to mitochondria-mediated toxicity. In this review, we describe recent studies addressing the following key questions: 1) Does Abeta accumulate in mitochondria of AD brain and AD mouse models? 2) How does Abeta gain access to the mitochondria? 3) If mitochondria are loaded with Abeta, do they develop similar evidence of dysfunction? 4) What are the mechanisms underlying mitochondrial Abeta-induced neuronal toxicity? and 5) What is the impact of interaction of mitochondrial Abeta with its binding partners (cyclophilin D and ABAD) on mitochondrial and neuronal properties/function in an Abeta milieu? The answers to these questions provide new insights into mechanisms of mitochondrial stress related to the pathogenesis of AD and information necessary for developing therapeutic strategy for AD.
线粒体功能障碍是阿尔茨海默病（AD）的早期特征。线粒体特性的异常包括能量代谢受损、关键呼吸酶活性/功能缺陷、线粒体活性氧物质的积累/产生以及膜通透性转换孔的形成。虽然线粒体功能障碍的机制尚不完全清楚，但最近的研究为线粒体中 Abeta 的进行性积累提供了大量证据，这与线粒体介导的毒性直接相关。在这篇综述中，我们描述了最近的研究，以回答以下关键问题：1）Abeta 是否在 AD 大脑和 AD 小鼠模型的线粒体中积累？2）Abeta 如何进入线粒体？3）如果线粒体中充满了 Abeta，它们是否会出现类似的功能障碍证据？4）线粒体 Abeta 诱导神经元毒性的机制是什么？以及 5）在 Abeta 环境中，线粒体 Abeta 与其结合伙伴（亲环素 D 和 ABAD）的相互作用对线粒体和神经元的特性/功能有什么影响？这些问题的答案为与 AD 发病机制相关的线粒体应激机制提供了新的见解，并为开发 AD 治疗策略提供了必要的信息。
