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患者大脑淀粉样蛋白形成中的意义，我们在体外检测了似乎由早老素突变诱导的γ分泌酶抑制是否改变了膜脂水平，包括作为淀粉样蛋白形成诱导剂的GM1-神经节苷脂。在药物抑制γ-分泌酶活性的情况下，分化的PC12细胞神经节苷脂的水平增加，包括Gm1-神经节苷脂，这是淀粉样蛋白形成的起始部位。这一结果表明，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.