Mancuso M, Orsucci D, Siciliano G, Murri L
Department of Neuroscience, Neurological Clinic, University of Pisa, Italy.
Curr Alzheimer Res. 2008 Oct;5(5):457-68. doi: 10.2174/156720508785908946.
To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The mitochondria play central role in the bioenergetics of the cell and apoptotic cell death. In the past 20 years research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders, including AD. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress and accumulation of Abeta, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria in the cascade of events leading to AD, and we will try to provide an answer to the question "what comes first".
迄今为止，β淀粉样蛋白（Aβ）级联假说仍是阿尔茨海默病（AD）的主要发病机制模型，但其在大多数散发性AD病例中的作用尚不清楚。线粒体在细胞生物能量学和凋亡性细胞死亡中起核心作用。在过去20年里，研究一直致力于阐明线粒体的参与情况以及线粒体氧化磷酸化缺陷在包括AD在内的晚发性神经退行性疾病中的作用。已有报道称，在多个AD组织中线粒体存在形态、生化和基因异常。在AD患者的大脑、血小板和成纤维细胞中观察到线粒体呼吸受损，尤其是细胞色素C氧化酶（COX）缺乏。“线粒体级联假说”可以解释散发性AD的许多生化、遗传和病理特征。线粒体DNA（mtDNA）的体细胞突变可能导致能量衰竭、氧化应激增加和Aβ积累，这会形成恶性循环，加剧mtDNA损伤和氧化应激。尽管有证据表明AD中线粒体功能障碍，但迄今为止尚未检测到mtDNA的致病突变。事实上，关于mtDNA单倍群在AD中作用的研究结果存在争议。在这篇综述中，我们讨论了线粒体在导致AD的一系列事件中的作用，并试图回答“先发生什么”这个问题。
