Molecular mechanism of endoplasmic reticulum stress and Alzheimer disease

我们以前的研究表明早老素-1突变细胞的内质网应激反应下调。根据淀粉样蛋白级联假说，我们对研究内质网应激对淀粉样蛋白-β肽（Aβ）生成的影响产生了兴趣。在本研究中，我们发现用ER应激物处理导致Aβ 40和Aβ 42生成减少。免疫细胞化学和亚组分免疫印迹显示，内质网应激导致淀粉样前体蛋白（amyloid precursor protein，APP）在分泌途径中从晚期区室移位到早期区室，并降低了β和γ切割释放的Aβ水平，尽管其分泌酶活性没有降低。免疫共沉淀研究表明，ER应激反应促进BiP/GRP 78与APP的结合，以保留在早期区室，如ER。在ER应激的显性阴性细胞中，Aβ的还原系统可能恶化，导致Aβ的相对积聚。这些结果表明，通过ER应激诱导BiP/GRP 78可能是Aβ产生的一种调节机制。

Our previous reports showed that endoplasmic reticulum (ER) stress response was down-regulated in presenilin-1 mutant cells. Following the amyloid cascade hypothesis, we developed an interest in investigating the effects of ER stress on amyloid-β peptide (Aβ) generation. In the present study, we showed that treatment with an ER stressor resulted in the reduction of Aβ 40 and Aβ 42 generation. Immunocytochemical study and immunoblotting of subfractions showed that ER stress caused dislocation of amyloid precursor protein (APP) from late compartments to early compartments during the secretory pathway, and decreased levels of released Aβ by β and γ cutting despite no reduction of its secretase activities. Co-immunoprecipitation study showed that ER stress response facilitated binding of BiP/GRP78 to APP to be retained in early compartments, such as ER. In dominant-negative cells for ER stress, the reduction system of Aβ may deteriorate to cause relative accumulation of Aβ. These findings suggest that induction of BiP/GRP78 by ER stress may be one regulatory mechanism for Aβ generation.