Alzheimer’s disease (AD) is the most common type of senile dementia, characterized by neurofibrillary tangle and amyloid plaque in brain pathology. Major efforts in AD drug were devoted to the interference with the production and accumulation of amyloid-β peptide (Aβ), which plays a causal role in the pathogenesis of AD. Aβ is generated from amyloid precursor protein (APP), by consecutive cleavage by β-secretase and γ-secretase. Therefore, β-secretase and γ-secretase inhibition have been the focus for AD drug discovery efforts for amyloid reduction. Here, we review β-secretase inhibitors and γ-secretase inhibitors/modulators, and their efficacies in clinical trials. In addition, we discussed the novel concept of specifically targeting the γ-secretase substrate APP. Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD.

阿尔茨海默病（AD）是最常见的老年痴呆症，其特征是脑部病理学中的神经原纤维缠结和淀粉样斑块。AD药物的主要研究方向是干扰β淀粉样肽（Aβ）的产生和积累，Aβ在AD的发病机制中起着因果作用。Aβ 由淀粉样前体蛋白 (APP) 通过 β-分泌酶和 γ-分泌酶连续裂解而产生。因此，β-分泌酶和γ-分泌酶抑制一直是减少淀粉样蛋白的AD药物研发工作的重点。在这里，我们回顾一下 β-分泌酶抑制剂和 γ-分泌酶抑制剂/调节剂及其在临床试验中的疗效。此外，我们还讨论了特异性靶向γ-分泌酶底物APP的新概念。针对 APP 的淀粉样蛋白形成过程仍然是开发改善疾病的 AD 疗法的基本合理策略，并且 γ-分泌酶/APP 复合物结构的最新进展为设计 AD 选择性抑制剂/调节剂提供了新的机会。