Aged animals develop some of the behavioral and brain abnormalities that occur in elderly humans, including individuals with Alzheimer's disease (AD). The character, cellular participation, molecular mechanisms, and evolution of these abnormalities can be investigated in animal models that reproduce certain features of the human condition. We propose to identify the ways in which alterations in neurotransmitter systems contribute to impairments in cognitive and motor performance through prospective behavioral/neurobiological studies of aged rodents and retrospective analyses of a behaviorally well-characterized cohort of aged nonhuman primates. In aged rats, we hypothesize that cognitive/memory deficits will be linked to abnormalities of cholinergic and, possibly, catecholaminergic and glutamatergic systems, whereas motor impairments will correlate with perturbations of the nigrostriatal system and, probably, other circuits in the basal ganglia. Similar behavioral/clinical-pathological correlations will be undertaken in monkeys. In addition, using tissues from aged monkeys, we will analyze the relationships between the performance of specific tasks and the distributions/densities of deposits of the amyloid beta peptide (Abeta) in brain regions essential for behavioral performance. Finally, we will use optimally prepared monkey tissues to define stages in the evolution and the cellular/molecular substrates of age-associated lesions, including the formation of neurites and Abeta and loss of synapses, in hippocampus and neocortex. This information, in conjunction with that obtained in Projects 1, 3, and 4, will be invaluable in defining therapeutic strategies for restoring functions of neuronal circuits critical for memory and movement and for ameliorating pathological processes that lead to the deposition of Abeta and the formation of senile plaques in the aged brain.
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