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？由于γ-分泌酶抑制剂被认为是阿尔茨海默病（AD）发病机制中必不可少的肽，因此γ-分泌酶抑制剂已成为AD的潜在药物靶点。然而，广谱的γ-分泌酶底物和两个主要的A？种A？40和A？42，在淀粉样蛋白病理学中的应用使得基于γ-分泌酶的治疗成为一个巨大的挑战。结合目前的γ-分泌酶生物学的理解，最近失败的临床试验要求需要开发γ-分泌酶抑制剂，专门阻止A？42生产而离开A？40和其他基板完整。我们已经确定了一系列的化合物，表现出这些特点，他们通过一个不同的机制，从A？42种γ-分泌酶调节剂。本申请的总体目标是阐明A？42-使用化学生物学、细胞生物学和动物模型的综合方法，特异性γ-分泌酶抑制。我们将开发一系列的光活化类似物，以探讨不同模式的A？42抑制。我们将确定它们的特异性，并使用新的细胞测定法和小鼠试验将其与其他类型的γ-分泌酶抑制剂进行比较。最后，我们将测试A？42对AD敲入小鼠模型中突触功能和认知的特异性抑制。总的来说，该提案使用创新的方法和模型系统来解决AD发病机制和治疗开发中非常重要的主题。

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.