GLUCOCORTICOIDS AND ALZHEIMER'S-LIKE HIPPOCAMPAL DAMAGE

糖皮质激素（GCs）的累积暴露是一个主要因素

Cumulative exposure to glucocorticoids (GCs) is a major determinant of the rate of hippocampal neuron loss during aging; moreover, GCs can impair the capacity of the hippocampus to survive varied neurological insults. Our ongoing work focuses on two themes: a) GCs exacerbate the toxicity of these hippocampal insults by exacerbating the "glutamate/NMDA/calcium" cascade of damage. b) These GC actions derive from the catabolic effects of GCs upon metabolism in these neurons. We are obtaining support for these ideas, and the present grant explores their implications. 1) If, as we find, GCs exacerbate this cascade, then GCS should also exacerbate calcium-dependent degenerative events in the hippocampus. Our pilot data strongly support this and we will explore this further, looking at GC modulation of calcium-dependent proteolysis of spectrin, and accumulation of tau and ubiquitin antigenicity. We will determine the physiological relevance of such GC modulation and its role in the senescent hippocampus. Work will be both in vivo and in primary hippocampal cultures. 2) A growing literature suggests that fragments of the amyloid precursor protein can be toxic to hippocampal neurons. Working both in vivo and in vitro, we will attempt to replicate reports regarding such toxicity, and then determine whether it is modulated by GCs. If so, we will explore the physiological relevance and role in hippocampal aging of such GC actions. 3) GCs inhibit glucose uptake in the hippocampus and depress concentrations of energy substrates. We will use a novel microphysiometer to detennine whether GCs depress metabolism in hippocampal neurons or accelerate the metabolic decline observed during neurological insults. We will also examine whether amyloid fragments depress metabolism as well.