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

淀粉样蛋白假说指出，改变了Abeta的产生或清除，导致Abeta的逐渐积累。 聚集的Abeta，这反过来又引发了导致阿尔茨海默病的级联事件。增加 证据支持高度淀粉样蛋白生成的A β 42同种型是致病性物种的概念。 因此，选择性靶向A β 42可能是治疗阿尔茨海默病的一种极好的抗淀粉样蛋白策略。 治疗学在目前的资金周期中，我们已经报道了一个非甾体抗炎药的子集， 非甾体类抗炎药（NSAID）选择性地降低A β 42，同时增加较短的A β种类，而不改变整体 A β水平，我们称之为γ-分泌酶调节作用的活动。此外，这些发现使我们 我推测，这种活动可能部分解释了慢性使用者的AD风险明显降低， 非甾体抗炎药。因此，NSAID代表了一类γ-分泌酶调节剂的原型成员 [GSM)在体外和体内选择性降低Abeta42。我们还提供了初步表征 它的潜在作用机制，我们现在认为是以γ-分泌酶复合物本身为中心， 包括APR衬底。在下一个资金周期，我们假设这种γ分泌酶 调节活性可以靶向初始ε-裂解位点，其似乎先于并且可能 预测各种Abeta肽在γ位点的裂解。我们将在培养的 细胞和体外膜制剂。此外，在与项目2合作的研究中，我们将 检查通过Abeta42降低剂总是增加的较短Abeta42肽的生物学。我们 将询问较短的Abeta肽是否具有神经毒性，以及它们是否调节毒性， 通过测试暴露后的突触传递和突触可塑性来测定A β 42肽的聚集性 这些肽。最后，我们将测试是否与降低GSM的Abeta42和 第二种不相关的化合物在降低淀粉样蛋白水平方面优于单一药物治疗，并且优于单一药物治疗的上级 APP转基因小鼠中淀粉样蛋白相关病理学。我们假设针对多个细胞 这些途径最终将比单一靶点更有效。我们希望我们的研究将被翻译成 如果我们能证明与联合治疗的协同作用，将来在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.