Department of Biochemistry, Institute of Post Graduate Medical Education & Research, Kolkata, India.
J Alzheimers Dis. 2011;27(4):753-65. doi: 10.3233/JAD-2011-110686.
The entangled relationship of brain aging, mitochondrial dysfunction, and amyloid-β peptide (Aβ₄₂) toxicity occupies the center stage in the pathogenesis of Alzheimer's disease (AD). The present study examines some of the toxic effects of Aβ₄₂ on brain mitochondria and provides evidence that aged brain mitochondria are significantly more vulnerable to Aβ₄₂ toxicity. In particular, the study has shown that the aggregated, but not the monomeric, form of Aβ₄₂ in varying concentrations (10-40 μM) during in vitro incubation causes a loss of mitochondrial membrane potential, a decrease in phosphorylation capacity and ATP synthesis, and the release of cytochrome c from the mitochondria but without any noticeable change in the activities of respiratory chain complexes. Such effects of Aβ₄₂ are strikingly more conspicuous on aged rat (22-24 months) brain mitochondria compared to that on brain mitochondria of young rats (4-6 months). More interestingly is the observation that in contrast to young rat brain mitochondria, a significantly higher level of Aβ₄₂ remains associated with aged brain mitochondria under basal incubation condition as well as after exposure to exogenously added peptide. Extrapolated to an in vivo scenario, the results have clear implications in AD pathogenesis and also partly explain why brain aging is a dominant risk factor for this disease condition.
脑老化、线粒体功能障碍和淀粉样β肽（Aβ₄₂）毒性的复杂关系在阿尔茨海默病（AD）的发病机制中占据中心地位。本研究考察了 Aβ₄₂对脑线粒体的一些毒性作用，并提供了证据表明衰老的脑线粒体对 Aβ₄₂毒性更敏感。特别是，该研究表明，在体外孵育过程中，以不同浓度（10-40 μM）存在的聚集但不是单体形式的 Aβ₄₂会导致线粒体膜电位丧失、磷酸化能力和 ATP 合成减少，以及细胞色素 c 从线粒体释放，但呼吸链复合物的活性没有明显变化。与年轻大鼠（4-6 个月）脑线粒体相比，Aβ₄₂对衰老大鼠（22-24 个月）脑线粒体的这些影响更为明显。更有趣的是观察到，与年轻大鼠脑线粒体相比，在基础孵育条件下以及在暴露于外源性添加肽后，Aβ₄₂与衰老脑线粒体的结合水平明显更高。推断到体内情况，这些结果对 AD 的发病机制有明确的影响，也部分解释了为什么脑老化是这种疾病的主要危险因素。
