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

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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.