Brain aging in rats and humans is accompanied by evidence of lysosomal abnormalities; these are particularly pronounced in AIzheimer's disease. Moreover, suppression of lysosomal proteases with drugs such as chloroquine or Z-Phe-Ala-diazomethylketone produces a diverse array of changes found in the aged brain. The proposed research will use a recently introduced cultured brain slice technique to test for interactions between lysosomal dysfunction and two other age-associated phenomena: pathogenesis and the accumulation of beta-amyloid containing peptides. Project One will determine if inhibition of lysosomal enzymes increases the vulnerability of hippocampus to an excitotoxin. Project Two will address the converse question; i.e., do excitotoxins enhance the effects of lysosomal dysfunction? Project Three will test if beta-amyloid 1-42 acts as a lysosomotropic agent when applied directly to cultured hippocampal slices. Finally, Project Four will test for synergisms between beta-amyloid 1-42 and lysosomal inhibition with regard to the production of age-related effects. These studies should provide information directly pertinent to the causes of pathogenesis in the aged brain and could provide a model system with which to explore potential therapeutic interventions.
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