CELLULAR MECHANISMS OF y-SECRETASE MODULATION AND EFFICACY OF COMBINATION TREATME

淀粉样蛋白假说指出，改变Abeta的产生或清除导致逐渐积累 聚集的Abeta，进而启动导致阿尔茨海默病的一连串事件。渐增 有证据支持高度淀粉样变性的Abeta42亚型是致病物种的概念。 因此，选择性靶向Abeta42可能是治疗阿尔茨海默氏症的良好的抗淀粉样蛋白策略 治疗学。在当前的资金周期中，我们已经报告了非类固醇抗炎药的一个子集 药物(非类固醇抗炎药)选择性地降低Abeta42，同时增加较短的Abeta物种，而不改变整体 β水平，一种我们称之为伽马分泌酶调节作用的活动。此外，这些发现使我们 IO假设，这种活动可能在一定程度上解释了长期使用 非甾体抗炎药。因此，非甾体抗炎药代表了一类伽马分泌酶调节剂的原型成员 在体外和体内选择性降低Abeta42的[GSM]。我们还提供了对 其潜在的作用机制，我们现在认为是以伽马分泌酶复合体本身为中心的， 包括APR底物。在下一个资金周期中，我们假设这种伽马分泌酶 调节活性可能以最初的epsilon-裂解位点为靶点，它似乎先于并可能 预测不同的Abeta多肽在伽马部位的裂解。我们将在培养的细胞中检验这一假设 细胞和体外膜制剂。此外，在与项目2合作进行的研究中，我们将 检查较短的Abeta多肽的生物学特性，这些多肽总是被Abeta42降压剂增加。我们 将询问较短的Abeta多肽是否具有神经毒性，以及它们是否调节毒性和 暴露后突触传递和突触可塑性检测Abeta42肽的聚集性 这些多肽。最后，我们将测试与Abeta42联合治疗是否降低GSM和a 第二种无关化合物在降低淀粉样蛋白水平方面优于单一药物治疗，并且 APP转基因小鼠的淀粉样蛋白相关病理。我们假设以多个细胞为目标 路径最终将比单一目标更有效。我们希望我们的研究成果能被翻译成 如果我们能证明联合治疗的协同作用，我们将在未来的AD受试者中进行测试。

The amyloid hypothesis states that altered Abeta production or clearance leading to gradual accumulation of aggregated Abeta, which in turn initiates the cascade of events leading to Alzheimer's disease. Increasing evidence supports the concept that the highly amyloidogenic Abeta42 isoform is the pathogenic species. Consequently, selective targeting of Abeta42 may be an excellent anti-amyloid strategy for Alzheimer's therapeutics. In the current funding cycle, we have reported that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) selectively lower Abeta42 while increasing shorter Abeta species without altering overall Abeta levels, an activity which we term gamma-secretase modulating action. Further, these findings led us io hypothesize that this activity may in part explain the apparent AD risk reduction in chronic users of NSAIDs. Thus, NSAIDs represent the prototypic members of a class of gamma-secretase modulators [GSM) that selectively lower Abeta42 in vitro and in vivo. We also provided preliminary characterization of its potential mechanism of action, which we now believe is centered on the gamma-secretase complex itself, including the APR substrate. In the next funding cycle, we hypothesize that this gamma-secretase modulating activity may target the initial epsilon-cleavage site, which appears to precede and possibly predict the cleavage of various Abeta peptides at the gamma-site. We will test this hypothesis in cultured cells and with in vitro membrane preparations. Further, in studies in collaboration with Project 2, we will examine the biology of shorter Abeta peptides that are invariably increased by Abeta42 lowering agents. We will ask whether shorter Abeta peptides are neurotoxic and whether they modulate the toxicity and aggregability of Abeta42 peptide by testing synaptic transmission and synaptic plasticity following exposure to these peptides. Finally, we will test whether combination treatments with Abeta42 lowering GSMs and a second unrelated compound are superior to treatment with single agents in reducing amyloid levels and amyloid associated pathology in APP transgenic mice. We hypothesize that targeting multiple cellular pathways will ultimately be more efficacious than single targets. We hope that our studies will be translated to testing in AD subjects in the future if we can demonstrate synergy with combination treatments.