Increased amyloid-beta 42(43) in brains of mice expressing mutant presenilin 1
Increased amyloid-beta 42(43) in brains of mice expressing mutant presenilin 1
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DOI：
10.1038/383710a0
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发表时间：
1996-10-24
期刊：
影响因子：
64.8
通讯作者：
Younkin, S
中科院分区：
文献类型：
--
作者：
Duff, K;Eckman, C;Younkin, S
已知编码淀粉样β前体蛋白（APP）（1）、早老素1（PS1）（2）和早老素2（PS2）（3，4）的基因突变可引起早发性常染色体显性阿尔茨海默病。对来自这些突变受试者的血浆和成纤维细胞的研究已经确定，它们都改变淀粉样β蛋白（β APP）加工，通常导致淀粉样β蛋白的分泌（相对分子质量4，000; M（r）4K;类似于90% A β 1-40，类似于10% A β 1-42（43）），因此A β 42（43）的细胞外浓度增加（5）。A β 42的这种增加被认为是启动阿尔茨海默病发病机制的关键变化，因为A β 42（43）早期并选择性地沉积在老年斑中，这些老年斑在患有所有形式的疾病的患者的大脑中观察到。为了证实早老素突变增加了大脑中A β 42的量，并测试早老素突变是否作为真正的显性（功能获得），我们现在构建了表达野生型和突变型早老素基因的小鼠。对这些小鼠的分析表明，突变型而非野生型PS1的过表达选择性地增加脑A β 42（43）。这些结果表明，早老素突变可能通过增加大脑中A β 42的量而导致阿尔茨海默病。
MUTATIONS in the genes encoding amyloid-beta precursor protein (APP)(1), presenilin 1 (PS1)(2) and presenilin 2 (PS2)(3,4) are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid beta-protein (beta APP) processing, which normally leads to the secretion of amyloid-beta protein (relative molecular mass 4,000; M(r) 4K; similar to 90% A beta 1-40, similar to 10% A beta 1-42(43)), so that the extracellular concentration of A beta 42(43) is increased(5). This increase in A beta 42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because A beta 42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of A beta 42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain A beta 42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of A beta 42(43) in the brain.