Molecular mechanisms of gamma-secretase modulation central to Alzheimer’s disease

阿尔茨海默病（AD）是一种进行性神经退行性疾病，是痴呆的主要原因，对医疗保健系统和社会造成了巨大的损失。虽然AD的发病机制知之甚少，但其中心是所谓的β-淀粉样蛋白（Aβ）肽的产生，其由膜内蛋白酶γ-分泌酶从淀粉样前体蛋白（APP）产生。事实上，γ-分泌酶的催化亚基的突变改变了Aβ的产生谱并导致家族性AD，使蛋白酶成为开发治疗或预防阿尔茨海默病的疗法的有希望的靶点。具体地，开发可以修饰γ-分泌酶活性以选择性地减少致病性β-淀粉样蛋白种类的形成而不影响γ-分泌酶的总体活性的药剂代表了靶向AD的有吸引力的策略。尽管在研究γ-分泌酶方面取得了重大进展，但我们仍然不了解其催化活性和特异性如何在机制水平上调节。在拟议的项目中，我们将采用一种新的方法，并利用新的试剂来研究γ-分泌酶及其调节。使用跨学科的方法，我们的目标是阐明细胞环境和外部因素如何在分子水平上调节γ-分泌酶。我们还将描述γ-分泌酶的新工具和试剂，并定义其作用机制。总的来说，这些研究将为γ-分泌酶调节提供急需的见解，并为阿尔茨海默病的发病机制和治疗开发提供分子基础。

Alzheimer’s disease (AD), a progressive neurodegenerative disease and leading cause of dementia, exacts a tremendous toll on both the healthcare system and society broadly. Although the pathogenesis of AD is poorly understood, it centers on the production of so-called β-amyloid (Aβ) peptides, which are produced from amyloid precursor protein (APP) by the intramembrane protease γ-secretase. Indeed, mutations in the catalytic subunit of γ-secretase alter Aβ production profile and cause familial AD, making the protease a promising target for developing therapies to treat or prevent Alzheimer’s Disease. Specifically, developing agents that can modify γ- secretase activity to selectively reduce the formation of pathogenic β-amyloid species without affecting γ- secretase’s overall activity represent an attractive strategy to target AD. Despite significant progress in studying γ-secretase, we still do not understand how its catalytic activity and specificity are modulated at a mechanistic level. In the proposed project, we will apply a new approach and leverage novel reagents to investigate γ- secretase and its modulation. Using an interdisciplinary approach, we aim to elucidate how the cellular context and external factors modulate γ-secretase at the molecular level. We will also characterize new tools and reagents for γ-secretase and define their mechanism of actions. Collectively, the proposed studies will provide much needed insights into γ-secretase modulation and offer a molecular basis for Alzheimer’s disease pathogenesis and therapeutic development.