Aging, Energy and Alzheimer’s Disease

Abstract

The most important risk factor for Alzheimer’s disease (AD) is increasing age. However, the mechanism by which increasing age contributes to an increase in risk is unknown. One possibility is that a decline in oxidative phosphorylation may occur due to progressive impairment of mitochondrial function. Mitochondrial DNA is particularly susceptible to oxidative damage due to its lack of protective histones, its limited repair mechanisms, and its close relationship to the inner mitochondrial membrane, where free radicals are generated. Consistent with these findings, we and others have found progressive increases in mitochondrial deletions with normal aging in human postmortem brain tissue. The increase in deletions is most marked in the putamen, whereas the cerebellum, which has a lower metabolic rate, shows fewer deletions. We also made direct measurements of oxidative damage to both mitochondrial and nuclear DNA in human postmortem brain tissue. We measured the amounts of 8-hydroxy-2-deoxyguanosine, one of approximately 20 modified bases which occur following oxidative damage to DNA. These measurements showed progressive increases in oxidative damage to both nuclear and mitochondrial DNA with aging in human brain. A key issue is whether these changes are accompanied by any functional changes. Prior studies showed a progressive decrease in mitochondrial complex I and complex IV activity with normal aging in human muscle biopsies. We examined the activity of the mitochondrial oxidative phosphorylation enzymes in cortical tissue of 20 rhesus monkeys across the life span of this species. These studies showed a progressive decline in complex I and complex IV activity with normal aging, yet complex II—III and complex V activities were unaffected. This finding is consistent with the observation that several functionally important complex I and complex IV subunits are encoded by mitochondrial DNA, whereas complex II—III subunits are mostly encoded by nuclear DNA. In collaborative studies, we found a small number of point mutations in mitochondrial DNA in Alzheimer’s disease patients, which may exacerbate age-related declines in activity of mitochondrial enzymes. We hypothesize that such declines in mitochondrial enzyme activity may facilitate excitotoxicity or other pathologic processes. In the context of AD, impaired mitochondrial function may lead to increased generation of free radicals, which may oxidize β -amyloid and enhance its aggregation. This may also produce a form of β -amyloid which is neurotoxic. We have examined the effects of intracortical injections of s-amyloid or control peptides in both young and old rhesus monkeys. Although β -amyloid was not toxic in young monkeys, it produced neurotoxic effects in old monkeys. Age-related declines in energy metabolism may therefore serve as an important risk factor for amyloid deposition and toxicity in AD.