The overall goals of this project are to analyze the basic cellular mechanisms through which peripheral calcium (Ca) regulatory hormones influence Ca influx into, and homeostasis within, brain neurons; to unravel the basis for the apparent age-related increase in the susceptibility of brain neurons to peripheral hormonal effects, and the third is to relate these changes to neurons that are at risk of aging-related death. This project directly complements Projects 5 and 1, which are investigating peripheral hormonal phosphate/calcium in AD subjects, and brain steroid receptors in AD tissues, respectively. There presently is evidence for a role only of glucocorticoids (GCs) in neuronal death during the brain aging process, and/or for the modulation of Ca currents in hippocampal neurons. Consequently, this project will focus first on the mechanisms of the GC- neuronal Ca homeostasis linkage. In addition, however, it will also determine whether and how other Ca regulatory hormones for which there are specific brain receptors (e.g., the active vitamin D metabolite (1,25- (OH)2D3), parathyroid hormone (PTH) and calcitonin) act on brain Ca currents/homeostasis. A series of electrophysiological voltage clamp methods, including single ion channel studies of calcium currents in dissociated hippocampal neurons and cell cultures will be used, along with experimental interventions that alter intracellular second messengers, to analyze the mechanisms underlying hormonal effects on hippocampal calcium currents. The functional relevance to brain aging and neuronal death will be assessed, by comparisons in aged vs young rat hippocampal neurons, by comparisons of neurons at risk for age-related death (CA1 pyramidal cells) to neurons that are relatively protected against death (dentate granule cells), and by studies of long- term exposure of cell cultures to altered hormonal milieus, in relation to neuronal viability and Ca current changes. Aging-related changes in hormonal regulation of calcium currents could represent an aging susceptibility factor that predisposes neurons to degeneration, both in normal aging, and particularly in Alzheimer's disease.
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