Wolfe Michael S
Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, 66045, USA.
Neurochem Res. 2019 Jan;44(1):5-11. doi: 10.1007/s11064-018-2511-1. Epub 2018 Apr 4.
Genetics strongly implicate the amyloid β-peptide (Aβ) in the pathogenesis of Alzheimer's disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer's disease (FAD). As presenilin is the catalytic component of the γ-secretase protease complex that produces Aβ from APP, mutation of the enzyme or substrate that produce Aβ leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that presenilins are dysfunctional in FAD. γ-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function-the carboxypeptidase trimming of initially formed long Aβ peptides containing most of the transmembrane domain to shorter secreted forms-is an emerging common feature of FAD-mutant γ-secretase complexes.
遗传学有力地表明，淀粉样β肽（Aβ）与阿尔茨海默病的发病机制密切相关。早老素和淀粉样前体蛋白（APP）中的显性错义突变会导致早发性家族性阿尔茨海默病（FAD）。由于早老素是γ-分泌酶蛋白酶复合体的催化成分，该复合体从APP产生Aβ，产生Aβ的酶或底物的突变会导致FAD。然而，早老素突变导致FAD的机制一直存在争议，功能获得和功能丧失被视为两种二元选择。相反，本综述将阐述早老素在FAD中功能失调的情况。γ-分泌酶是一种多功能酶，它以复杂且连续的方式对APP跨膜结构域进行蛋白水解。一种特定功能的降低——将最初形成的包含大部分跨膜结构域的长Aβ肽羧肽酶修剪为较短的分泌形式——是FAD突变型γ-分泌酶复合体的一个新出现的共同特征。
