The long-term goal of this project is to determine the mechanism of selective neuronal death in aging and AD. This project tests the hypothesis that glucocorticoids interact with calcium regulatory proteins, producing neural dysfunction and cell death. This hypothesis arises from studies in aged animals demonstrating that prolonged exposure to glucocorticoids contributes to age-related neuronal cell death as well as from studies linking altered calcium homeostasis to age-related neural dysfunction. A more general version of this hypothesis is to be examined: an increase in the ratio of proteins that favor an increase in intracellular [Ca] (e.g., GCRll and L-type calcium channels) relative to those proteins that reduce, buffer or extrude calcium (e.g., Ca, Mg-ATPase, protein kinase C and calbindin-D28k) occurs in brain cells that are most at risk for degeneration in aging and AD. This project will specifically address 1) the neuroanatomical co-localization and quantitative ratio of GCRll relative to calcium regulatory proteins in the aging rat hippocampus, 2) quantitatively analyze age-related changes in mRNA expression for GCRll and calcium regulatory proteins in rat hippocampus, 3) test the acute and long-term regulation of GCRll and calcium regulatory proteins as a function of aging, and 4) determine potential interactions between intracellular calcium, calcium regulatory proteins and GCRll in the dysfunction of AD. Progress along these lines of research will test a novel hypothesis in AD - the glucocorticoid/calcium dyshomeostasis hypothesis of cell death, in addition to testing the glucocorticoid system and the calcium regulatory system independently. Even if these two systems are not linked, the proposed studies will yield the first systematic and comprehensive examination of two presently viable hypotheses (GCs and Ca regulation) of age-related neuronal loss in relation to specific pathological alterations in aging and the AD brain.
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