LINKS BETWEEN PROTEOLYTIC PROCESSING AND BRAIN AGING

大鼠和人的脑老化伴随着溶酶体的证据 异常；这些在艾兹海默氏症中尤为明显。 此外，溶酶体蛋白水解酶的抑制药物，如 氯喹或Z-苯丙氨酸-重氮甲基酮可产生多种不同的 在老化的大脑中发现的变化。拟议的研究将使用最近的 引入培养脑片技术来测试 溶酶体功能障碍和另外两种与年龄相关的现象：发病机制 以及含有β-淀粉样蛋白的多肽的积累。项目一将 确定抑制溶酶体酶是否会增加易感性 海马体对一种刺激性毒素。项目二将解决相反的问题 问题：即，兴奋性毒素是否增强溶酶体的作用？ 功能障碍？项目三将测试β-淀粉样蛋白1-42是否起到 溶酶促进剂直接应用于培养的海马片。 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年龄相关的产生 效果。这些研究应提供与以下方面直接相关的信息 老年性脑损伤的发病机制及模型研究 探索潜在治疗干预措施的系统。

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.