Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
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DOI：
10.1038/34910
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发表时间：
1998-01-22
期刊：
影响因子：
64.8
通讯作者：
Van Leuven, F
中科院分区：
文献类型：
--
作者：
De Strooper, B;Saftig, P;Van Leuven, F
早老素-1基因(PS1)的点突变是家族性阿尔茨海默病的主要原因，它们导致淀粉样前体蛋白(APP)(1-4)的蛋白分解过程选择性地增加淀粉样多肽-β(1-42)的产生。在这里，我们研究了PS1是否也参与了来自PS1缺陷小鼠胚胎的神经元培养中正常的APP处理。没有PS1，APP胞外区的α-和β-分泌酶(5)的裂解不受影响，而APP跨膜区的伽马-分泌酶的裂解被阻止，导致APP的羧基末端片段积累，淀粉样肽的产量下降5倍。脉冲追逐实验表明，PS1缺乏特异性地降低了APP膜相关片段的周转率。正如通过膜结合转录因子(6)的蛋白分解来调节胆固醇代谢一样，PS1似乎促进了切割APP完整膜结构域的蛋白分解活性。我们的结果表明，临床上出现的PS1突变导致功能增强，抑制PS1活性是阿尔茨海默病抗淀粉样变性治疗的潜在靶点。
Point mutations in the presenilin-1 gene (PS1) are a major cause of familial Alzheimer's disease, They result in a selective increase in the production of the amyloidogenic peptide amyloid-beta(1-42) by proteolytic processing of the amyloid precursor protein (APP)(1-4). Here we investigate whether PS1 is also involved in normal APP processing in neuronal cultures derived from PS1-deficient mouse embryos. Cleavage by alpha- and beta-secretase(5) of the extracellular domain of APP was not affected by the absence of PS1, whereas cleavage by gamma-secretase of the transmembrane domain of APP was prevented, causing carboxyl-terminal fragments of APP to accumulate and a fivefold drop in the production of amyloid peptide. Pulse-chase experiments indicated that PS1 deficiency specifically decreased the turnover of the membrane-associated fragments of APP. As in the regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor(6), PS1 appears to facilitate a proteolytic activity that cleaves the integral membrane domain of APP. Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.