Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe D J
Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Nat Med. 1997 Jan;3(1):67-72. doi: 10.1038/nm0197-67.
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.
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生成性Aβ42肽水平升高，Aβ42肽是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基因的表达均未改变APP水平、α和β分泌酶活性以及Aβ生成。在转染细胞中，PS1和PS2突变导致所有突变克隆中Aβ42分泌显著增加。同样，突变型而非野生型PS1转基因小鼠在大脑中显示出Aβ42的显著过量产生，并且这种效应早在2至4个月龄时就可检测到。不同的PS突变对Aβ生成有不同的影响。Aβ42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获得，并可能通过增强Aβ42的产生诱导AD，从而促进脑β淀粉样变性。
