Mitochondria in aging and Alzheimer's disease.
Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta 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-beta 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-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-beta. 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-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta 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.
Crouch
P J
PJ
Department of Pathology, The University of Melbourne, Melbourne, Australia.
Cimdins
K
K
Duce
J A
JA
Bush
A I
AI
Trounce
I A
IA
D000368:Aged; D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D008136:Longevity; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress
D000682:Amyloid; D004272:DNA, Mitochondrial