γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43
γ-Secretase Modulators and Presenilin 1 Mutants Act Differently on Presenilin/γ-Secretase Function to Cleave Aβ42 and Aβ43
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DOI：
10.1016/j.celrep.2012.11.028
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发表时间：
2013-01-01
期刊：
影响因子：
8.8
通讯作者：
Takeda, Masatoshi
中科院分区：
文献类型：
--
作者：
Okochi, Masayasu;Tagami, Shinji;Takeda, Masatoshi
解读A β 42（43）相对于总A β比例的调节机制是理解阿尔茨海默病（AD）病因学的核心;然而，由家族性突变和γ-分泌酶调节剂（GSMs）引起的A β 42（43）比例变化的潜在机制尚不清楚。在这里，我们在体外和活细胞中显示，早老素（PS）/γ-分泌酶将A β 42切割成A β 38，A β 43切割成A β 40或A β 38。大约40%的A β 38来自A β 43。A β 42（43）裂解参与活细胞中A β 42（43）比率的调节。GSMs增加PS/γ-分泌酶结合的A β 42的切割（增加k（cat））并减缓其从酶的解离（降低k（B）），而PS1突变体和反向GSMs显示相反的效果。因此，我们提出了一个概念来描述A β 42（43）的产生过程，并提出GSM如何起作用，我们认为PS/γ-分泌酶切割A β 42（43）的功能丧失可能引发AD，并可能代表治疗靶点。
Deciphering the mechanism by which the relative A beta 42(43) to total A beta ratio is regulated is central to understanding Alzheimer disease (AD) etiology; however, the mechanisms underlying changes in the A beta 42(43) ratio caused by familial mutations and gamma-secretase modulators (GSMs) are unclear. Here, we show in vitro and in living cells that presenilin (PS)/gamma-secretase cleaves A beta 42 into A beta 38, and A beta 43 into A beta 40 or A beta 38. Approximately 40% of A beta 38 is derived from A beta 43. A beta 42(43) cleavage is involved in the regulation of the A beta 42(43) ratio in living cells. GSMs increase the cleavage of PS/gamma-secretase-bound A beta 42 (increase k(cat)) and slow its dissociation from the enzyme (decrease k(b)), whereas PS1 mutants and inverse GSMs show the opposite effects. Therefore, we suggest a concept to describe the A beta 42(43) production process and propose how GSMs act, and we suggest that a loss of PS/gamma-secretase function to cleave A beta 42(43) may initiate AD and might represent a therapeutic target.