AGING VULNERABILITY TO EXCITATORY AMINO ACIDS

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This research program is directed towards an understanding of the neurochemical and behavioral correlates of the decline in cognition and memory with age and in Alzheimer's Disease (AD). The ultimate goal is the development of preventative or ameliorative treatments for this decline. The investigations focus on age-associated changes in the rat nucleus basalis magnocellularis (NBM), an area analogous to the nucleus basalis of Meynert in humans. During normal aging and in AD the brain develops a complicated pattern of degenerative changes including, but not limited to, the loss of specific neural systems that underlie the normal mechanisms associated with memory. The loss of cells in the nucleus basalis of Meynert may be responsible for this memory impairment. The nature of the selection process that leads to the degeneration of cells within the NBM is unknown, although endogenous excitatory amino acids have been implicated. In addition, the identity of the cell, or cells, in this nucleus whose degeneration leads to the development of the memory impairment, is also unknown. The assumption has been that the loss of cholinergic cells is sufficient to produce the memory deficit. Previous research from this laboratory has raised significant doubt about the validity of this assumption. However, the NBM region contains many noncholinergic neurotransmitter systems and their role in age- and dementia-associated memory deficits has not been investigated. This project addresses the following hypothesis related to the mechanisms of NBM neuronal cell death associated with aging: if neurons in the NBM demonstrate an age-related differential vulnerability to excitatory amino acid neurotoxins, such as 2-amino-3-hydroxy-5-methylisoxazole-4- proprionicacid (AMPA) or N-methyl-d-aspartate (NMDA), then these neurotoxins should produce differential behavioral and biochemical consequences in young, adult and old rats. This hypothesis will be tested by producing lesions within the basal forebrain of rats; studying the behavioral changes that develop; examining the histological and biochemical changes in the brain following the lesions; and correlating the changes in specific neuronal markers with performance in the behavioral tasks. These experiments have significant implications for our understanding of the differential vulnerability of specific NBM neurons with aging.