Impairments in cognitive/memory and motor functions are common in the elderly, and severe deficits in these domains occur in Alzheimer's disease (AD), Parkinson's disease (PD), and many other less-common neurodegenerative disorders. In these settings, clinical manifestations are determined by degeneration of neuronal circuits, particularly cholinergic, dopaminergic, and glutamatergic neurons, that subserve memory and motor functions. Using newly available antibodies that recognize receptor subtypes (Project 1), the distributions of receptors will be identified in these circuits. The localization of these receptors to specific cells is critical in the interpretation of studies that correlate behavioral impairments with alterations in circuits in aged animals (Project 2). Because some of these neurons are responsive to neurotrophins, the distributions of neurotrophins/neurotrophin receptors will be analyzed in these systems, and links between neurotrophin- synthesizing cells and potentially responsive nerve cells will be documented by retrograde transport of labeled peptides. This information is critical for studies of the effects of these factors on neuronal populations that undergo experimental degeneration (Project 4). In Project 2, age-associated cognitive/motor deficits will be correlated with perturbations of transmitter circuits in aged animals. Aged monkeys that show deposits of the amyloid beta peptide (Abeta) will be used to analyze the cellular events that lead to neurite formation, Abeta deposition, and alterations in synaptic density. Abeta is derived by aberrant processing from a larger amyloid precursor (APP), and overexpression of APP-751 and mutations in APP play critical roles in amyloidogenesis. In Project 3, transgenic mice with overexpression of APP-751 or with AD-type APP mutations will be studied with molecular, biochemical, and neuropathological approaches. In Project 4, we will test the effects of neurotrophins on behavior/neuronal biology in aged animals and in animals that show retrograde degeneration of subsets of neurons, studies that will provide new information concerning the usefulness of neurotrophic factors in treating human neurological disorders.
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