Caspersen Casper, Wang Ning, Yao Jun, Sosunov Alexander, Chen Xi, Lustbader Joyce W, Xu Hong Wei, Stern David, McKhann Guy, Yan Shi Du
Department of Surgery, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA.
FASEB J. 2005 Dec;19(14):2040-1. doi: 10.1096/fj.05-3735fje. Epub 2005 Oct 6.
Although amyloid-beta peptide (Abeta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease (AD), mechanisms through which intracellular Abeta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular Abeta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. Abeta progressively accumulates in mitochondria and is associated with diminished enzymatic activity of respiratory chain complexes (III and IV) and a reduction in the rate of oxygen consumption. Importantly, mitochondria-associated Abeta, principally Abeta42, was detected as early as 4 months, before extensive extracellular Abeta deposits. Our studies delineate a new means through which Abeta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.
尽管β-淀粉样肽（Aβ）是与阿尔茨海默病（AD）发病机制相关的神经毒性物质，但细胞内Aβ损害细胞特性并导致神经元功能障碍的机制仍有待阐明。在此我们证明，在突变型人淀粉样前体蛋白靶向神经元过表达的转基因小鼠和AD患者的大脑线粒体中存在细胞内Aβ。Aβ在线粒体中逐渐积累，并与呼吸链复合物（III和IV）的酶活性降低以及氧消耗率降低有关。重要的是，早在4个月时就检测到了与线粒体相关的Aβ，主要是Aβ42，此时细胞外Aβ广泛沉积之前。我们的研究描绘了一种新的途径，通过该途径Aβ可能损害神经元能量代谢，导致AD中的细胞功能障碍。
