Statins inhibit the dimerisation of {beta}-secretase via both isoprenoid- and cholesterol-mediated mechanisms

Richard B Parsons (1) , Gemma C Price , Joanna K Farrant , Daryl Subramaniam , Jubril Adeagbo-Sheikh , Brian M Austen

1 Basic Medical Sciences

We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of {beta}-amyloid, the dimerisation of {beta}-secretase and its trafficking into cholesterol-rich microdomains. As statins influence these lipid modifications in addition to their effects upon cholesterol biosynthesis, we have investigated the effects of lovastatin and simvastatin at a range of concentrations chosen to distinguish different cellular effects upon {beta}-amyloid production and {beta}-secretase structure and its localisation in bHEK cells. We have compared the changes brought about by statins to those brought about by the palmitoylation inhibitor cerulenin and the farnesyltransferase inhibitor CVFM. The statin-mediated reduction in A{beta} production correlated with an inhibition of {beta}-secretase dimerisation into its more active form at all concentrations of statins investigated. These effects were reversed by the administration of mevalonate, showing that these effects were mediated via hydroxymethylglutaryl-CoenzymeA-dependent pathways. At low (1{mu}M) statin concentrations, reduction in A{beta} production and inhibition of {beta}-secretase dimerisation was mediated by inhibition of isoprenoid synthesis. At high (>10{mu}M) 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, {beta}-amyloid release from cells was markedly higher at 50{mu}M simvastatin than at 1{mu}M, whereas these concentrations resulted in similar reductions in total {beta}-amyloid production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer‘s disease.

Mots clés: Life Sciences

Richard B Parsons, Gemma C Price, Joanna K Farrant, Daryl Subramaniam, Jubril Adeagbo-Sheikh, et al.. Statins inhibit the dimerisation of {beta}-secretase via both isoprenoid- and cholesterol-mediated mechanisms. Biochemical Journal, 2006, 399 (2), pp.205-214. ⟨10.1042/BJ20060655⟩. ⟨hal-00478587⟩