Cordy Joanna M, Hooper Nigel M, Turner Anthony J
Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, UK.
Mol Membr Biol. 2006 Jan-Feb;23(1):111-22. doi: 10.1080/09687860500496417.
The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).
阿尔茨海默病中发生的淀粉样蛋白生成代表了一种与膜相关的基本病理过程，涉及一种由整合膜蛋白酶（分泌酶）代谢的膜结合底物。因此，在阿尔茨海默病患者大脑中作为斑块在细胞外积累的β淀粉样肽（Aβ），是由整合跨膜淀粉样前体蛋白（APP）的顺序蛋白水解切割产生的。β分泌酶或BACE-1（β位点APP切割酶）是一种跨膜天冬氨酸蛋白酶，负责这些切割事件中的第一步，产生可溶性APP胞外域sAPPβ和一个C端片段CTFβ。CTFβ随后被γ分泌酶复合物切割，早老素是该复合物的催化核心，以产生Aβ。各种研究表明，胆固醇是调节Aβ产生的一个重要因素，高胆固醇水平与Aβ生成和沉积增加有关。然而，目前这种作用的潜在机制尚不清楚。最近的证据表明，淀粉样蛋白生成性APP加工可能优先发生在称为脂筏的富含胆固醇的膜区域，并且胆固醇水平的变化可能通过改变膜内APP切割酶的分布来发挥其作用。脂筏可能参与Aβ的聚集，也参与其被诸如纤溶酶或可能的中性内肽酶（NEP）等淀粉样蛋白降解酶的清除。
