Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice
Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice
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DOI：
10.1038/nm0197-67
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发表时间：
1997-01-01
期刊：
影响因子：
82.9
通讯作者：
Selkoe, DJ
中科院分区：
文献类型：
--
作者：
Citron, M;Westaway, D;Selkoe, DJ
早老素（PS）基因突变导致最具侵袭性的早发性阿尔茨海默病（AD）的机制尚不清楚，但突变携带者的成纤维细胞分泌的淀粉样蛋白A β（42）肽水平增加，这是AD斑块的主要成分。我们建立了共表达人PS和淀粉样β蛋白前体（APP）基因的转染细胞和转基因小鼠模型，并定量分析了PS表达对APP加工的影响。在这两种模型中，野生型PS基因的表达并没有改变APP水平，α和β分泌酶活性和A β的生产。在转染的细胞中，PS1和PS2突变导致所有突变克隆中A β（42）分泌的高度显著增加。同样地，突变型而非野生型PS1转基因小鼠在脑中显示出A β（42）的显著过量产生，并且这种效应早在2-4个月大时就可检测到。不同的PS突变对A β产生有不同的影响。A β（42）增加的程度与早老素表达水平无关。我们的数据表明，早老素突变导致功能的显性增益，并可能通过增强A β（42）的产生诱导AD，从而促进脑β淀粉样变性。
The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta(42) peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta(42) secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta(42) in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta(42) increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta(42) production, thus promoting cerebral beta-amyloidosis.