Mechanism and therapy of AB-42-specific gamma-secretase

描述（由申请人提供）：由于γ -分泌酶在A？肽被认为在阿尔茨海默病（AD）的发病机制中至关重要，γ -分泌酶抑制剂已成为AD的潜在药物靶点。然而，γ -分泌酶底物的广谱性和两种主要A？物种,一个?40和A？在淀粉样蛋白病理学中，基于γ -分泌酶的治疗是一个艰巨的挑战。当前对γ -分泌酶生物学的理解与最近失败的临床试验相结合，要求开发特异性阻断A？42生产离开A？40等基材完好无损。我们已经确定了一系列具有这些特征的化合物，它们的作用机制与a ？42种分泌酶调节剂。本应用的首要目标是阐明A？利用化学生物学、细胞生物学和动物模型的综合方法研究42特异性γ -分泌酶抑制。我们将开发一系列光激活类似物来探索不同模式的a ？42抑制。我们将确定它们的特异性，并将它们与其他类型的γ分泌酶抑制剂进行比较，使用新型细胞试验和小鼠试验。最后，我们将测试A？AD敲入小鼠模型对突触功能和认知的特异性抑制。总的来说，本提案使用创新的方法和模型系统来解决AD发病机制和治疗发展中非常重要的主题。

DESCRIPTION (provided by applicant): Due to the critical role of gamma-secretase in the generation of A? peptides, which are believed to be essential in Alzheimer's disease (AD) pathogenesis, gamma-secretase inhibitors have emerged as potential drug targets for AD. However, the wide spectrum of gamma-secretase substrates and the differential activities of the two major A? species, A?40 and A?42, in amyloid pathology have made gamma-secretase based therapy a formidable challenge. The combination of current understanding of the gamma-secretase biology with the recently failed clinical trial calls for the need to develop gamma-secretase inhibitors that specifically block A?42 production while leaving A?40 and other substrates intact. We have identified a series of compounds that exhibit these characteristics and they act through a distinct mechanism from that of A?42 gamma-secretase modulators. The overarching goal of this application is to elucidate the mechanism of action and therapeutic efficacy of A?42-specific gamma-secretase inhibition using an integrated approach of chemical biology, cell biology and animal models. We will develop a series of photoactivatable analogs to probe the molecular mechanisms of different mode of A?42 inhibition. We will determine their specificity and compare these with other classes of gamma-secretase inhibitors using novel cellular assays and in mice. Lastly, we will test the efficacy of A?42 specific inhibition on synaptic function and cognition in an AD knock-in mouse model. Overall, this proposal uses innovative approaches and model systems to address a topic highly significant in AD pathogenesis and therapeutic development.