Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92037.
Mol Biol Cell. 2021 Feb 1;32(3):247-259. doi: 10.1091/mbc.E20-05-0345. Epub 2020 Dec 9.
Amyloid beta (Aβ) is a major component of amyloid plaques, which are a key pathological hallmark found in the brains of Alzheimer's disease (AD) patients. We show that statins are effective at reducing Aβ in human neurons from nondemented control subjects, as well as subjects with familial AD and sporadic AD. Aβ is derived from amyloid precursor protein (APP) through sequential proteolytic cleavage by BACE1 and γ-secretase. While previous studies have shown that cholesterol metabolism regulates APP processing to Aβ, the mechanism is not well understood. We used iPSC-derived neurons and bimolecular fluorescence complementation assays in transfected cells to elucidate how altering cholesterol metabolism influences APP processing. Altering cholesterol metabolism using statins decreased the generation of sAPPβ and increased levels of full-length APP (flAPP), indicative of reduced processing of APP by BACE1. We further show that statins decrease flAPP interaction with BACE1 and enhance APP dimerization. Additionally, statin-induced changes in APP dimerization and APP-BACE1 are dependent on cholesterol binding to APP. Our data indicate that statins reduce Aβ production by decreasing BACE1 interaction with flAPP and suggest that this process may be regulated through competition between APP dimerization and APP cholesterol binding.
淀粉样蛋白β（Aβ）是淀粉样斑块的主要成分，也是阿尔茨海默病（AD）患者大脑中发现的关键病理标志物。我们表明，他汀类药物可有效减少来自非痴呆对照受试者、家族性 AD 和散发性 AD 受试者的人神经元中的 Aβ。Aβ 通过 BACE1 和 γ-分泌酶的顺序蛋白水解从淀粉样前体蛋白（APP）衍生而来。虽然先前的研究表明胆固醇代谢调节 APP 加工为 Aβ，但机制尚不清楚。我们使用 iPSC 衍生的神经元和转染细胞中的双分子荧光互补测定来阐明改变胆固醇代谢如何影响 APP 加工。使用他汀类药物改变胆固醇代谢会降低 sAPPβ 的产生并增加全长 APP（flAPP）的水平，表明 BACE1 对 APP 的加工减少。我们进一步表明，他汀类药物降低了 flAPP 与 BACE1 的相互作用，并增强了 APP 二聚化。此外，他汀类药物诱导的 APP 二聚化和 APP-BACE1 的变化取决于 APP 与胆固醇的结合。我们的数据表明，他汀类药物通过减少 BACE1 与 flAPP 的相互作用来降低 Aβ 的产生，并表明该过程可能通过 APP 二聚化和 APP 胆固醇结合之间的竞争来调节。
