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Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein (see comments)

机译：Presenilin-1的缺乏会抑制淀粉样蛋白前体蛋白的正常切割（请参阅评论）

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摘要

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). 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 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, 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.
机译：presenilin-1基因（PS1）中的点突变是家族性阿尔茨海默氏病的主要原因。他们通过淀粉样蛋白前体蛋白（APP）的蛋白水解处理，选择性增加了淀粉样蛋白生成肽淀粉样蛋白β（1-42）的产量。在这里，我们调查PS1是否也参与源自PS1缺陷小鼠胚胎的神经元培养物中的正常APP处理。缺少PS1不会影响APP胞外域的α-和β-分泌酶的切割，而阻止了APP跨膜结构域的γ-分泌酶的切割，导致APP的羧基末端片段积聚并增加了五倍。淀粉样肽产量下降。脉冲追踪实验表明，PS1缺乏会特别降低APP的膜相关片段的周转率。就像通过膜结合的转录因子的蛋白水解调节胆固醇代谢一样，PS1似乎促进了蛋白水解活性，该活性可以切割APP的完整膜结构域。我们的结果表明，临床上表现出的PS1突变会导致功能增强，并且抑制PS1活性是阿尔茨海默氏病抗淀粉样生成疗法的潜在目标。

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