title: Statins inhibit the dimerization of beta-secretase via both isoprenoid- and cholesterol-mediated mechanisms.
abstract: We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of Abeta (amyloid beta-peptide), the dimerization of beta-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 Abeta production and beta-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 Abeta production correlated with an inhibition of beta-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 microM) statin concentrations, reduction in Abeta production and inhibition of beta-secretase dimerization were mediated by inhibition of isoprenoid synthesis. At high (>10 microM) concentrations of statins, inhibition of beta-secretase palmitoylation occurred, which we demonstrated to be regulated by intracellular cholesterol levels. There was also a concomitant concentration-dependent change in beta-secretase subcellular trafficking. Significantly, Abeta release from cells was markedly higher at 50 microM SIMVA than at 1 microM, whereas these concentrations resulted in similar reductions in total Abeta production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer's disease.
authors.affiliation: Department of Basic Medical Sciences, St. Georges, University of London, Cranmer Terrace, London SW17 0RE, UK. r.parsons@sgul.ac.uk
authors.forename: Richard B
authors.initials: RB
authors.lastname: Parsons
authors.forename: Gemma C
authors.initials: GC
authors.lastname: Price
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Farrant
authors.forename: Daryl
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Jubril
authors.initials: J
authors.lastname: Adeagbo-Sheikh
authors.forename: Brian M
authors.initials: BM
authors.lastname: Austen
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D019281:Dimerization; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D008954:Models, Biological; D008970:Molecular Weight; D019308:Palmitic Acid / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013729:Terpenes / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000960:Hypolipidemic Agents; D013729:Terpenes; D019308:Palmitic Acid; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D008798:Mevalonic Acid