GLUCOCORTICOIDS AND ALZHEIMER'S-LIKE HIPPOCAMPAL DAMAGE

累积暴露于糖皮质激素（GC）是一个主要的 衰老过程中海马神经元丢失率的决定因素; 此外，GC可以损害海马体的能力， 在各种神经损伤中存活 我们正在进行的工作重点是 两个主题：a）GC加剧了这些海马神经元的毒性， 通过加剧“谷氨酸/NMDA/钙”级联反应， 损害B）这些GC作用源自以下物质的分解代谢作用： GC在这些神经元中的代谢。 我们正在获得支持 对于这些想法，目前的赠款探索他们的 影响 第一章 如果像我们发现的那样，GC加剧了这种级联反应，那么GCS应该 也加重了钙依赖性退行性事件， 海马体。 我们的试点数据强烈支持这一点，我们将 进一步探讨这一点，看看GC调制 血影蛋白的钙依赖性蛋白水解和tau的积累 和遍在蛋白抗原性。 我们将确定 这种GC调节的相关性及其在衰老中的作用 海马体。 工作将在体内和原代海马 cultures. （二） 越来越多的文献表明淀粉样蛋白的片段 前体蛋白可能对海马神经元有毒。 工作 在体内和体外，我们将尝试复制报告 关于这种毒性，然后确定它是否 由GC调节。 如果是这样，我们将探讨生理 相关性和作用，海马老化的GC行动。 第三章 GC抑制海马中的葡萄糖摄取， 能量基质的浓度。 我们会用一本小说 微生理计，以确定GC是否抑制代谢， 海马神经元或加速观察到的代谢下降 在神经损伤期间。 我们还将检查淀粉样蛋白 碎片也会抑制新陈代谢。

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.