Statins inhibit the dimerization of β-secretase via both isoprenoid- and cholesterol-mediated mechanisms

Author:

Parsons Richard B.1,Price Gemma C.1,Farrant Joanna K.1,Subramaniam Daryl1,Adeagbo-Sheikh Jubril1,Austen Brian M.1

Affiliation:

1. Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London SW17 0RE, U.K.

Abstract

We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of Aβ (amyloid β-peptide), the dimerization of β-secretase and its trafficking into cholesterol-rich microdomains. As statins influence these lipid modifications in addition to their effects on cholesterol biosynthesis, we have investigated the effects of lovastatin and SIMVA (simvastatin) at a range of concentrations chosen to distinguish different cellular effects on Aβ production and β-secretase structure and its localization in bHEK cells [HEK-293 cells (human embryonic kidney cells) transfected with the Asp-2 gene plus a polyhistidine coding tag] cells. We have compared the changes brought about by statins with those brought about by the palmitoylation inhibitor cerulenin and the farnesyltransferase inhibitor CVFM (Cys-Val-Phe-Met). The statin-mediated reduction in Aβ production correlated with an inhibition of β-secretase dimerization into its more active form at all concentrations of statin investigated. These effects were reversed by the administration of mevalonate, showing that these effects were mediated via 3-hydroxy-3-methylglutaryl-CoA-dependent pathways. At low (1 μM) statin concentrations, reduction in Aβ production and inhibition of β-secretase dimerization were mediated by inhibition of isoprenoid synthesis. At high (>10 μM) concentrations of statins, inhibition of β-secretase palmitoylation occurred, which we demonstrated to be regulated by intracellular cholesterol levels. There was also a concomitant concentration-dependent change in β-secretase subcellular trafficking. Significantly, Aβ release from cells was markedly higher at 50 μM SIMVA than at 1 μM, whereas these concentrations resulted in similar reductions in total Aβ production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer's disease.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

Cited by 41 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3