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脑中淀粉样蛋白形成中的意义，我们检测了γ-分泌酶抑制（似乎由早老素突变诱导）是否改变了膜脂质的水平，包括GM 1-神经节苷脂，它是体外淀粉样蛋白形成的诱导剂。在γ-分泌酶活性的药理学抑制下，神经节苷脂（包括GM 1-神经节苷脂）的水平在分化的PC 12细胞的神经炎末端（淀粉样蛋白形成的起始位点）增加。这一结果表明，临床早老素突变可通过改变脑内膜脂环境诱导淀粉样蛋白形成。

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.