LINKS BETWEEN PROTEOLYTIC PROCESSING AND BRAIN AGING

大鼠和人类的大脑老化伴随着溶酶体的证据， 异常;这些在阿尔茨海默病中特别明显。 此外，用药物如 氯喹或Z-Phe-Ala-重氮甲基酮产生各种各样的 老年大脑的变化。这项研究将使用最近 引入了培养的脑切片技术来测试 溶酶体功能障碍和另外两种年龄相关现象：发病机制 以及含有β-淀粉样蛋白的肽的积累。项目一将 确定溶酶体酶的抑制是否会增加脆弱性 兴奋毒素的反应项目二将解决匡威的问题 问题;即，兴奋性毒素是否增强了溶酶体 功能障碍项目三将测试β-淀粉样蛋白1-42是否作为一种 当直接应用于培养的海马切片时， 最后，项目四将测试β-淀粉样蛋白1-42之间的协同作用， 和溶酶体抑制有关的生产年龄相关的 方面的影响.这些研究应提供直接相关的信息， 老年脑组织发病的原因，并可提供一个模型 探索潜在治疗干预的系统。

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.