Biochem. J. (2006) 399
(205–214) (Printed in Great Britain)
Statins inhibit the dimerization of b-secretase via both isoprenoid- and cholesterol-mediated mechanisms
Richard B. PARSONS1, Gemma C. PRICE, Joanna K. FARRANT, Daryl SUBRAMANIAM, Jubril ADEAGBO-SHEIKH and Brian M. AUSTEN
Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London SW17 0RE, U.K.
Key words: Alzheimer's disease, amyloid b-peptide (Ab), cholesterol, dimerization, palmitoylation, b-secretase, statin.
We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of Ab (amyloid b-peptide), the dimerization of b-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 Ab production and b-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 Ab production correlated with an inhibition of b-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 Ab production and inhibition of b-secretase dimerization were mediated by inhibition of isoprenoid synthesis. At high (>10 µM) concentrations of statins, inhibition of b-secretase palmitoylation occurred, which we demonstrated to be regulated by intracellular cholesterol levels. There was also a concomitant concentration-dependent change in b-secretase subcellular trafficking. Significantly, Ab release from cells was markedly higher at 50 µM SIMVA than at 1 µM, whereas these concentrations resulted in similar reductions in total Ab production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer's disease.
Abbreviations used: AD, Alzheimer's disease; APP, amyloid precursor protein; ATORVA, atorvastatin; Ab, amyloid b-peptide; BACE, b-site amyloid-cleaving enzyme; buffer R, reducing Laemmli sample buffer; buffer NR, non-reducing Laemmli sample buffer; HEK-293 cells, human embryonic kidney cells; bHEK cells, HEK-293 cells transfected with the Asp-2 gene plus a polyhistidine coding tag; ER, endoplasmic reticulum; GPI, glycosylphosphatidylinositol; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HRP, horseradish peroxidase; LOVA, lovastatin; MA, mevalonate; PA, palmitic acid; SIMVA, simvastatin; TGN, trans-Golgi network.
1To whom correspondence should be addressed (email r.parsons@sgul.ac.uk).
Received 3 May 2006/26 June 2006; accepted 28 June 2006
Published as BJ Immediate Publication 28 June 2006, doi:10.1042/BJ20060655
The Biochemical Society, London ©2006
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