Neurotoxic amyloid-β peptide (Aβ) 42/43 species generated by β-secretase and γ-secretase from the β-amyloid precursor protein (APP) are believed to trigger Alzheimer's disease (AD). Relative increases of these species due to mutations in APP and presenilin/γ-secretase are associated with the vast majority of early onset familial AD cases. Important breakthroughs have recently been made in elucidating the mechanism(s) of these mutations, showing that altered substrate interactions and substrate-enzyme complex stabilities are underlying their pathogenic Aβ generation. Moreover, first structures of γ-secretase in complex with APP and Notch1 substrates allow insight into how substrate cleavage could be initiated and further progress has been made in the mechanistic understanding of γ-secretase modulators, advanced Aβ-lowering drugs. These insights could be exploited for future AD clinical trials.

中文翻译：

---

家族性阿尔茨海默氏病的致病性Aβ产生：新颖的机理见解和治疗意义。

由β-淀粉样蛋白前体蛋白（APP）的β-分泌酶和γ-分泌酶产生的神经毒性淀粉样β-肽（Aβ）42/43被认为可触发阿尔茨海默氏病（AD）。由于APP和早老素/γ-分泌酶突变引起的这些物种的相对增加与绝大多数早期发病的家族性AD病例有关。最近在阐明这些突变的机制方面取得了重要突破，表明改变的底物相互作用和底物酶复合物稳定性是其致病性Aβ产生的基础。此外，与APP和Notch1底物复合的γ-分泌酶的第一个结构可以深入了解如何启动底物裂解，并且在对γ-分泌酶调节剂，先进的Aβ降低药物的机理理解上取得了进一步的进展。