of work:
The aim of this project is to assess the effects of aging at a behavioral level of analysis, to identify neurobiological mechanisms associated with these effects, and to evaluate interventions that might alter age-related performance decrements. Rodent models are tested in a battery of sensorimotor and learning/memory tasks. Neurochemical and neurohistological assays are conducted to determine neurobiological correlates of functional losses. Interventions include dietary restriction, various pharmacologic treatments, and gene transfer via adenoviral vectors. Multiple genotypes and genetically modified mice are examined to determine possible genetic involvement in age-related behavioral impairment. We have identified various effective pharmacologic strategies for improving learning performance of aged rats using manipulations of the cholinergic and glutamatergic neurotransmitter systems. Recently we have evaluated several novel inhibitors of butyrylcholinesterase to enhance the action of acetylcholine and observed improved maze learning in aged rats. Similar effects were observed following long-term treatment with a novel spin trap agent, which reduces oxidative stress in the brain. Regarding glutamate neurotransmission, we saw no effects on learning in aged rats following chronic treatment with a novel inhibitor of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspartyl-glutamate) to N-acetyl-aspartate and glutamate. The lack of effects was important for confirming the safety of this compound for the treatment of stroke. Using transgenic mice with mutations in the amyloid precursor protein (APP) gene and the presenilin-1 (PS1) gene as a model of Alzheimer's disease (AD), we have noted that treatment with acetylcholinesterase and butyrylcholinesterase inhibitors reduce production of APP and its peptide, beta-amyloid (AB). We are currently evaluating the ability of these compounds to reduce the AB plaque formation in brain observed in AD. In the same mice we have noted that estrogen treatment can reduce plaque formation as well as microglia activation. Regarding the dopamine system, we have begun long-term studies to evaluate whether motor deficits observed in a null mutant mouse in which the dopamine D2 receptor has been knocked out can be ameliorated by intrastriatal injections of a D2 adenoviral vector.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000302-17
Application #
6431418
Study Section
(LCMB)
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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