Mitochondrial Aβ:: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease
Mitochondrial Aβ:: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease
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DOI：
10.1096/fj.05-3735fje
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发表时间：
2005-10-01
期刊：
影响因子：
4.8
通讯作者：
Yan, SD
中科院分区：
文献类型：
--
作者：
Caspersen, C;Wang, N;Yan, SD
虽然淀粉样β肽（A β）是参与阿尔茨海默病（AD）发病机制的神经毒性物质，但细胞内A β损害细胞特性，导致神经元功能障碍的机制仍有待阐明。在这里，我们证明了细胞内A β存在于转基因小鼠和AD患者脑中的线粒体中，这些小鼠具有突变型人淀粉样前体蛋白的靶向神经元过表达。A β在线粒体中逐渐积累，并与呼吸链复合物（III和IV）的酶活性降低和氧消耗速率降低有关。重要的是，早在广泛的细胞外A β沉积之前的4个月，就检测到了与A β相关的A β，主要是A β 42。我们的研究描绘了一种新的方式，通过这种方式，A β可能损害神经元能量，导致AD中的细胞功能障碍。
Although amyloid-beta peptide (A beta) is the neurotoxic species implicated in the pathogenesis of Alzheimer's disease ( AD), mechanisms through which intracellular A beta impairs cellular properties, resulting in neuronal dysfunction, remain to be clarified. Here we demonstrate that intracellular A beta is present in mitochondria from brains of transgenic mice with targeted neuronal overexpression of mutant human amyloid precursor protein and AD patients. A beta 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 A beta, principally A beta 42, was detected as early as 4 months, before extensive extracellular A beta deposits. Our studies delineate a new means through which A beta potentially impairs neuronal energetics, contributing to cellular dysfunction in AD.