Guo Q, Christakos S, Robinson N, Mattson M P
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA.
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3227-32. doi: 10.1073/pnas.95.6.3227.
Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid beta-peptide (Abeta). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Abeta, and potentiated by mutant PS-1, were suppressed in calbindin-overexpressing cells. Impairment of mitochondrial function by Abeta (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by calbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.
早老素1（PS-1）基因突变是早发型常染色体显性遗传性阿尔茨海默病的常见病因。最近的研究结果表明，PS-1突变可能使神经元对因营养因子缺失和暴露于β淀粉样肽（Aβ）而诱导的细胞凋亡敏感。我们现在报告，钙结合蛋白钙结合蛋白D28k的过表达可防止表达突变型PS-1（L286V和M146V错义突变）的培养神经细胞发生凋亡。在过表达钙结合蛋白的细胞中，Aβ诱导的细胞内Ca2+浓度升高和活性氧生成（并由突变型PS-1增强）受到抑制。Aβ对线粒体功能的损害（先于细胞凋亡）因PS-1突变而加剧，而钙结合蛋白在很大程度上可预防这种损害。这些发现表明，PS-1突变通过一种涉及细胞钙稳态失衡的机制使神经元易发生凋亡，这会导致氧化应激和线粒体功能障碍。
