Mitochondria in Aging and Alzheimer's Disease

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Abstract
Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-β peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-β rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-β has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-β. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-β in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-β is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-β. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-β precursor protein, contributing to a loss of amyloid-β precursor protein functionality and increased amyloid-β production. Importantly, recent data show that amyloid-β accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease.

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