During the past five years a canine model of aging has been evaluated, with emphasis on categorization of cognitive decline and links with neuropathology. We have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in brain pathology. We specifically propose that working memory, and learning that involves abstract rules and requires flexibility, are particularly sensitive to age. These age sensitive functions are likely to depend on cortical circuits that converge in the prefrontal cortex. We further hypothesize that age-related impairment is partially attributable to oxidative stress that begins in middle age and triggers a cascade of events resulting in both accumulation of neurotoxic substances, such as beta-amyloid (A beta) protein and possibly cell dysfunction or death. The present proposal seeks first to extend our evaluation of the canine model and establish the cognitive processes that are particularly sensitive to aging, using both cross sectional and longitudinal strategies. Second, we propose to analyze key endpoints in an oxidative stress cascade that may be part of a sequence of neuropathological events underlying age-related impairment. Third, as a test of theory, we will use an intervention study to modify oxidative stress levels in dogs. Thus, this proposal incorporates a new component, to test the cognitive and neurobiological effects of intervention with a diet rich in a broad spectrum of antioxidants. This component of the proposal incorporates both a short-term (cross-sectional) and a long-term (longitudinal study) of cognition and brain aging in the dog. Specifically, direct measures of protein, lipid and DNA/RNA oxidation will be examined in control and treated animals along with hypothesized downstream consequences of oxidation serving as indirect measures, e.g., increased A beta, increased DNA strand breaks, caspase levels/activation and altered synaptic density. Overall, this project should provide unique insight into the role of oxidative damage and subsequent molecular cascades on the progression of brain aging and cognitive decline.
Showing the most recent 10 out of 65 publications
