Alzheimer's disease: role of aging in pathogenesis.
Alzheimer's disease (AD) is characterized by intraneuronal fibrillary tangles, plaques, and cell loss. Brain lesions in both sporadic AD (SAD) and familial AD (FAD) are the same, and in the same distribution pattern, as those in individuals with Down syndrome (DS) and in smaller numbers in nondemented older individuals. Dementia onset is around 40 years for DS, 40-60 years for FAD, and usually over 60 years for SAD. The different categories of AD may be due to processes that augment to different degrees the innate cellular aging rate, that is, mitochondrial superoxide radical (SO) formation. Thus, they increase the rate of accumulation of AD lesions. This lowers the age of onset into the dementia ranges associated with DS, FAD, and SAD, and concomitantly shortens life spans. Faster aging lowers AD onset age by decreasing the onset age for neurofibrillary tangle formation and neuronal loss, and the age when brain intercellular H2O2 can activate microglial cells. The early AD onset in DS is attributed to a defective mitochondrial complex 1. The proteins associated with FAD and their normal counterparts undergo proteolytic processing in the endoplasmic reticulum (ER). The mutated compounds increase the ratio of betaA42 to betaA40 and likely also down-regulate the ER calcium (Ca2+) buffering activity. Decreases in ER Ca2+ content should increase the mitochondrial Ca2+ pool, thus enhancing SO formation. SAD may be due to increased SO formation caused by mutations in the approximately 1000 genes involved in mitochondrial biogenesis and function. The hypothesis suggests measures to prevent and treat.
Harman
Denham
D
Department of Medicine, University of Nebraska College of Medicine, Omaha, Nebraska 68198-4635, USA.
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D001921:Brain / Q000473:pathology; D006259:Craniocerebral Trauma / Q000503:physiopathology; D003704:Dementia / Q000503:physiopathology; D004314:Down Syndrome / Q000473:pathology / Q000503:physiopathology; D006801:Humans