Statins inhibit the dimerization of β-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.

Statins Promote the Degradation of Extracellular Amyloid β-Peptide by Microglia via Stimulation of Exosome-associated Insulin-degrading Enzyme (IDE) Secretion

“…Initial studies demonstrated that lowering of membrane cholesterol by statins results in decreased generation of A␤ by altering the subcellular transport, localization, and dimerization of either APP, secretases, or both (47)(48)(49)(50). Recent studies also support a predominant role of protein isoprenylation in the statin-mediated effects on APP processing and plaque pathology (16,17,19). However, there are also data indicating the lack of any positive effects of statins on A␤ levels, amyloid pathology, and Tau metabolism.…”

“…In addition to inhibition of cholesterol biosynthesis, statins also impair the generation of isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate that play important roles in the post-translational modifications of Rho and Rab proteins thereby regulating their localization and biological function. Isoprenoids have also been shown to affect A␤ generation, by modulating ␤-secretase as well as ␥-secretase cleavage of APP (16,17,19).…”

“…In addition to inhibition of cholesterol biosynthesis, statins also impair the generation of isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate that play important roles in the post-translational modifications of Rho and Rab proteins thereby regulating their localization and biological function. Isoprenoids have also been shown to affect A␤ generation, by modulating ␤-secretase as well as ␥-secretase cleavage of APP (16,17,19).Notably, apoE, a major genetic factor for sporadic AD, is one of the important lipoproteins involved in cholesterol shuttling between neurons and astrocytes and is involved in remodeling and reorganization of neuronal networks after injury (20). Extracellular A␤ in complex with lipoproteins such as apoE can be internalized via receptor-mediated endocytosis involving the low density lipoprotein (LDL) receptor or LDL receptorrelated protein or via receptor-independent pinocytosis, followed by proteolytic degradation (21,22).…”

Reduction of Brain β-Amyloid (Aβ) by Fluvastatin, a Hydroxymethylglutaryl-CoA Reductase Inhibitor, through Increase in Degradation of Amyloid Precursor Protein C-terminal Fragments (APP-CTFs) and Aβ Clearance

“…Although statins affect A␤ metabolism, their proposed mechanism of action on A␤ production is quite diverse as follows: up-regulation of ␣-secretase processing, down-regulation of ␤-secretase processing, down-regulation of ␥-secretase processing, modulation of APP trafficking, and up-regulation of APP-CTF degradation (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, it should be noted that these various mechanisms were demonstrated mostly by in vitro studies.…”

Neuroprotective Role of Statins in Alzheimer`s Disease: Anti-Apoptotic Signaling~!2009-02-06~!2010-04-04~!2010-06-22~!

“…A reduction in -secretase activity is also reported to be involved in amyloid processing disturbances triggered by statins. Work by Parsons et al, 2006, showed that statins may interfere with the dimerization of -secretase thus, lowering its activity and reducing the amounts of A produced. However, a linear dose-response was not observed.…”