The impact of clinical presenilin mutations on amyloid formation in the brains of familial Alzheimer disease

为了阐明临床早老素突变在家族性阿尔茨海默病大脑淀粉样蛋白形成中的意义，我们在体外研究了γ-分泌酶抑制（似乎是由早老素突变诱导的）是否会改变膜脂的水平，包括gm1 -神经节苷脂，它是淀粉样蛋白形成的诱导剂。在γ-分泌酶活性的药物抑制下，分化的PC12细胞的神经末梢（淀粉样蛋白形成的初始位点）神经节苷脂水平，包括gm1 -神经节苷脂水平升高。提示临床早老素突变可通过改变脑膜脂环境诱导淀粉样蛋白的形成。

To clarify the significance of clinical presenilin mutations in amyloid formation in the brains of familial Alzheimer disease, we examined whetherγ-secretase inhibition, which seems to be induced by the presenilin mutations, alters the levels of membrane lipids, including GM1-ganglioside, which is an inducer of amyloid formation, in vitro. Under pharmacological inhibition ofγ-secretase activity, levels of gangliosides, including GM1-ganglioside, increased at neuritic terminals, which are the initial sites of amyloid formation, of differentiated PC12 cells. This result suggests that clinical presenilin mutations can induce amyloid formation via the alteration of membrane lipid environment in brains.