alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease
alpha-secretase-derived product of beta-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease
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DOI：
10.1046/j.1471-4159.1997.69062494.x
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发表时间：
1997-12-01
影响因子：
4.7
通讯作者：
Checler, F
中科院分区：
文献类型：
--
作者：
Ancolio, K;Marambaud, P;Checler, F
最近的报道表明早老素（PS）1的错义突变可能是导致阿尔茨海默病（FAD）的主要早发性常见形式的原因。通过不同的组织病理学、细胞生物学和分子生物学方法获得的实验数据得出的结论是，这些PS1突变明显触发了42个氨基酸长的β-淀粉样肽（A β）的产生增加。在这里，我们表明，野生型PS1在HK 293细胞中的过表达增加了A β 40的分泌。相比之下，FAD连锁的PS1突变体触发A β 40和A β 42的分泌增加，但显然有利于后者的产生。我们还表明，野生型PSI的过表达增强α-分泌酶衍生的C-末端截短的β-淀粉样前体蛋白（APP α）的片段的恢复，而表达突变的PS1的转染子分泌的APP α的量显着降低时，与表达野生型PS1的细胞相比。当比较过表达野生型β-淀粉样前体蛋白和PS1或其突变的同源物M146 V-PS1的双转染子时，也观察到这种降低。总之，我们的数据表明，与FAD相关的PS突变不仅触发A β 42与总A β分泌的比率增加，而且伴随着APP α的产生下调。
Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familiar forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PS1 mutations clearly trigger an increased production of the 42-amino-acid-long species of beta-amyloid peptide (A beta). Here we show that overexpression of wild-type PS1 in HK293 cells increases A beta 40 secretion. By contrast, FAD-linked mutants of PS1 trigger increased secretion of both A beta 40 and A beta 42 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PSI augments the alpha-secretase-derived C-terminally truncated fragment of beta-amyloid precursor protein (APP alpha) recovery, whereas transfectants expressing mutated PS1 secrete drastically lower amounts of APP alpha when compared with cells expressing wild-type PS1. This decrease was also observed when comparing double transfectants overexpressing wild-type beta-amyloid precursor protein and either PS1 or its mutated congener M146V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of A beta 42 over total A beta secretion but concomitantly downregulate the production of APP alpha.