Mechanisms of Statin-mediated Inhibition of Small G-protein Function

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a β-amyloid (Aβ)-mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block Aβ-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor (RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest a mechanism by which statins inhibit the actions of Rho GTPases and attenuate Aβ-stimulated inflammation. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been reported to reduce the risk of Alzheimer disease. We have shown previously that statins inhibit a β-amyloid (Aβ)-mediated inflammatory response through mechanisms independent of cholesterol reduction. Specifically, statins exert anti-inflammatory actions through their ability to prevent the isoprenylation of members of the Rho family of small G-proteins, resulting in the functional inactivation of these G-proteins. We report that statin treatment of microglia results in perturbation of the cytoskeleton and morphological changes due to alteration in Rho family function. Statins also block Aβ-stimulated phagocytosis through inhibition of Rac action. Paradoxically, the statin-mediated inactivation of G-protein function was associated with increased GTP loading of Rac and RhoA, and this effect was observed in myeloid lineage cells and other cell types. Statin treatment disrupted the interaction of Rac with its negative regulator the Rho guanine nucleotide dissociation inhibitor (RhoGDI), an interaction that is dependent on protein isoprenylation. We propose that lack of negative regulation accounts for the increased GTP loading. Isoprenylation of Rac is also required for efficient interaction with the plasma membrane, and we report that statin treatment dramatically reduces the capacity of Rac to interact with membranes. These results suggest a mechanism by which statins inhibit the actions of Rho GTPases and attenuate Aβ-stimulated inflammation. The primary action of statins is the inhibition of HMG-CoA 2The abbreviations used are: HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; Aβ, β-amyloid; AD, Alzheimer disease; DMEM, Dulbecco's modified Eagle's medium; fAβ, fibrillar β-amyloid; FBS, fetal bovine serum; GDI, guanine nucleotide dissociation inhibitor; GGpp, geranylgeranyl pyrophosphate; GST, glutathione S-transferase; PAK, p21-activated protein kinase; PBS, phosphate-buffered saline; PIPES, 1,4-piperazinediethanesulfonic acid. reductase, blocking the de novo synthesis of cholesterol and resulting in lower plasma cholesterol levels (1Tobert J.A. Nat. Rev. Drug Discov. 2003; 2: 517-526Crossref PubMed Scopus (643) Google Scholar). However, recent observations demonstrate that statins have pleiotropic actions that are not dependent on cholesterol reduction (2Liao J.K. Laufs U. Annu. Rev. Pharmacol. Toxicol. 2004; 45: 89-118Crossref Scopus (1386) Google Scholar). Specifically, statins have been shown to inhibit vascular inflammation, enhance endothelial function, inhibit the proliferation of vascular smooth muscle, reduce platelet activation and aggregation, and increase atherosclerotic plaque stability. Many of these effects were postulated to arise from disruption of the actions of small G-proteins. Although blockade of HMG-CoA reductase prevents de novo synthesis of cholesterol, it also decreases the pools of intermediate metabolites in the biosynthetic pathway that have ancillary functions. The post-translational modification of various cellular proteins with the isoprenoids farnesyl pyrophosphate or geranylgeranyl pyrophosphate (GGpp) is negatively affected by statin-mediated inhibition of HMG-CoA reductase. Small G-proteins of the Ras superfamily are among the principal targets of statin actions because of their isoprenylation. This modification of small G-proteins is crucial for their regulation through protein-protein and protein-lipid interactions with their regulators and effectors (3Zhang F.L. Casey P.J. Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Scopus (1738) Google Scholar). Small G-proteins are involved in many cellular functions including cytoskeletal rearrangement, cell motility, phagocytosis, intracellular trafficking, transcriptional regulation, cell growth, and development (4Takai Y. Sasaki T. Matozaki T. Physiol. Rev. 2001; 81: 153-208Crossref PubMed Scopus (2061) Google Scholar). The Rho subfamily of small G-proteins regulates the actin-based cytoskeleton. Activation of RhoA, Rac, and Cdc42 leads to the formation of stress fibers, lamellipodia, and filopodia, respectively (5Mackay D.J. Hall A. J. Biol. Chem. 1998; 273: 20685-20688Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar). The Rho family also plays critical roles in inflammatory signal transduction cascades. RhoA, Rac, and Cdc42 participate in the signaling pathways required for the activity of NF-κB, leading to the induction of cytokines and chemokines (6Montaner S. Perona R. Saniger L. Lacal J.C. J. Biol. Chem. 1998; 273: 12779-12785Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Furthermore, the activation of NF-κB has been linked to Rho-dependent activation of the c-Jun NH2-terminal kinase/stress-activated protein kinase pathway (6Montaner S. Perona R. Saniger L. Lacal J.C. J. Biol. Chem. 1998; 273: 12779-12785Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 7Coso O.A. Chiariello M. Yu J.C. Teramoto H. Crespo P. Xu N. Miki T. Gutkind J.S. Cell. 1995; 81: 1137-1146Abstract Full Text PDF PubMed Scopus (1567) Google Scholar). Rac is essential for the assembly and activation of NADPH oxidase, which is responsible for the defensive production of reactive oxygen species (8Lambeth J.D. Nat. Rev. Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2466) Google Scholar). Although the pleiotropic effects of statins were first observed by cardiovascular biologists, many of the anti-inflammatory actions have been demonstrated in animal models of central nervous system diseases with an inflammatory component including multiple sclerosis and ischemic stroke (9Youssef S. Stuve O. Patarroyo J.C. Ruiz P.J. Radosevich J.L. Hur E.M. Bravo M. Mitchell D.J. Sobel R.A. Steinman L. Zamvil S.S. Nature. 2002; 420: 78-84Crossref PubMed Scopus (996) Google Scholar, 10Miida T. Hirayama S. Nakamura Y. J. Atheroscler. Thromb. 2004; 11: 253-264Crossref PubMed Scopus (95) Google Scholar, 11Stuve O. Youssef S. Steinman L. Zamvil S.S. Curr. Opin. Neurol. 2003; 16: 393-401Crossref PubMed Scopus (146) Google Scholar). Several epidemiological studies and small clinical studies have suggested that statins reduce the risk of developing Alzheimer disease (AD); however, this linkage remains controversial (12Jick H. Zornberg G.L. Jick S.S. Seshadri S. Drachman D.A. Lancet. 2000; 356: 1627-1631Abstract Full Text Full Text PDF PubMed Scopus (1586) Google Scholar, 13Rockwood K. Kirkland S. Hogan D.B. MacKnight C. Merry H. Verreault R. Wolfson C. McDowell I. Arch. Neurol. 2002; 59: 223-227Crossref PubMed Scopus (476) Google Scholar, 14Wolozin B. Kellman W. Ruosseau P. Celesia G.G. Siegel G. Arch. Neurol. 2000; 57: 1439-1443Crossref PubMed Scopus (1343) Google Scholar, 15Sparks D.L. Sabbagh M.N. Connor D.J. Lopez J. Launer L.J. Browne P. Wasser D. Johnson-Traver S. Lochhead J. Ziolwolski C. Arch. Neurol. 2005; 62: 753-757Crossref PubMed Scopus (384) Google Scholar). We reported that the anti-inflammatory actions of statins in Aβ-stimulated microglia are independent of cholesterol reduction but are a consequence of the reduction of cellular levels of the isoprenoid GGpp (16Cordle A. Landreth G. J. Neurosci. 2005; 25: 299-307Crossref PubMed Scopus (156) Google Scholar). These effects were reported to depend on the disruption of Rho family function, which was demonstrated to be the result of lack of isoprenylation of these G-proteins. Statins have clearly been demonstrated to disrupt G-protein functions, and this disruption, in turn, prevents various inflammatory responses. However, the specific effects statins have on G-protein regulation and localization have not been clearly delineated. We report that statin-mediated inhibition of isoprenylation prevented Rho family members from interacting with RhoGDI, resulting in increased levels of GTP-loaded G-proteins. Lack of isoprenylation also prevented translocation to the plasma membrane. These effects culminated in the functional inhibition of Rho-family G-proteins. We suggest that the salutary effects of statins in reducing the risk for AD may arise, in part, from inhibition of microglia-mediated inflammatory responses. Materials and Reagents—β-Amyloid (Aβ) peptides Aβ-(25-35) and Aβ-(1-42), purchased from the American Peptide Company (Sunnyvale, CA), were dissolved in sterile water at a of and for at to formation D. B. M. J. M. A. J. C. C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, A. U. S. A. PubMed Scopus Google Scholar, G. J. PubMed Scopus Google Scholar). and were from and the the statin was to its by it in statin to of by of of This was at to the statin was with and cholesterol were purchased from and and in The GGpp inhibitor was purchased from and in and was purchased from pyrophosphate was purchased from and dissolved in and were purchased from Rac and were purchased from and to and were from and cell were because of their ability to to fibrillar not of through mechanisms that are to in primary microglia J. Landreth G. J. Neurosci. 2004; PubMed Scopus Google Scholar, A. J. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, J.C. Landreth J. Neurosci. 2001; PubMed Google Scholar). were from American and in at and was with fetal bovine and the of cells were and in microglia were in Dulbecco's modified Eagle's at and The was with FBS, and cells were in which was with FBS, and were in at and The was with FBS, and phagocytosis was by and Landreth J. Landreth G. J. Neurosci. 2004; PubMed Scopus Google which the actions of primary cells were the was to and the cells were with or at and The cells were for in the or of fibrillar Aβ-(25-35) or were to the cells for been in bovine The of was used a of were with and of cells were on an cells were on in and in in the or of of and at and The cells were with in and in The cells were at with for and in was by of the cells with of at and from for The were on and were at or of GTP-loaded Small cells cells cells or cells were The cells were with or with or the of cholesterol, or GGpp at and The cells were and G-proteins were by the ability of the GTP-loaded species to interact with protein cells were with and by the of by were by at for at of the were by the Biochem. PubMed Scopus Google Scholar). Rac and were by the of of protein with of or for at The were with and in of but were not The were on and to and with Rac or of the cellular were to cellular levels of the small G-proteins. were a cells were The cells were with were with a by on for were by for at at and protein were the Biochem. PubMed Scopus Google Scholar). of cellular were with of protein A and of in a of The were for at and with in and were used to and to and with to the of Rac with loading was by the with were a Rac cells were and with at and We the cellular from J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). statin treatment for the cells were by in and PIPES, on for by of were by at for at The resulting was and for at at in a The resulting was and the and the was in were used to the and to were with to the of Rac in was by the and with the were a were and were a of A was used to Statin observed that microglia to statins cellular these microglia were with or for this treatment the cells were and with to statin the cells to their and of cells with and of the isoprenoid GGpp prevented the of cellular These results suggest that the morphological changes are due to the statin-mediated inhibition of isoprenylation. The actin-based cytoskeleton is through action of the Rho family of small G-proteins statin-mediated in cellular is due to the Rho family function to cytoskeletal and (4Takai Y. Sasaki T. Matozaki T. Physiol. Rev. 2001; 81: 153-208Crossref PubMed Scopus (2061) Google Scholar). Statins capacity of statin treatment to cellular to the effects of statins on function. of microglia to results in the induction of phagocytosis through a mechanism and be by statin treatment through inhibition of this J. Landreth G. J. Neurosci. 2004; PubMed Scopus Google Scholar). cells were with of statins for with the cells were to or for The of cells was and phagocytosis to levels at A and results were observed Aβ-(25-35) was used to phagocytosis and We inhibition of phagocytosis at of the of cells with the of HMG-CoA reductase, the statin-mediated inhibition of phagocytosis Furthermore, of isoprenylation with the geranylgeranyl inhibitor the actions of statins These demonstrate that statins disrupt Rac function perturbation of Aβ-stimulated The statin-mediated inhibition of phagocytosis to their effects on Rac activation in The cells have in intracellular signaling are and have levels of Rac is an regulator of the actin-based and these cells levels of Rac of statin-mediated We GTP loading by to GTP-loaded cells were with statins for by of we that treatment with and dramatically increased the GTP loading of Rac statin Rac was observed a by The lower to Rac species K. O. D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, S. L. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar). We were also to demonstrate that the GTP loading of was increased by treatment with statins We observed a increase in Rac GTP loading in microglia This response is not to myeloid lineage Rac GTP loading was also in cells and cells the ability of statin treatment to the of Rac to its is to cell including inflammatory and cell a of we that statin treatment in of cellular Rac which is in This is to be the result of of the proteins reported by K. O. D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). We the effects of the with various members of the cholesterol biosynthetic pathway to this effect was a consequence of the reduction of cholesterol or other in its biosynthetic pathway on statin-mediated increase in Rac GTP loading. cells were with with or the of of cholesterol, and the GTP loading of Rac was to be of cells was to be associated with levels of GTP-loaded Rac also the Rac that it the inhibition on isoprenylation. GGpp, the isoprenoid for the modification of Rac (3Zhang F.L. Casey P.J. Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Scopus (1738) Google to the of cells prevented Rac GTP loading in response to statin treatment of GGpp isoprenylation by treatment with the geranylgeranyl inhibitor increased GTP-loaded Rac, the effects of statins and These that statin-mediated blockade of isoprenylation leads to increased Rac GTP loading. the mechanisms the statin-mediated increase in GTP-loaded Rac, we the effects of statins on the interaction Rac and its regulator Rho family G-proteins Rac are to negative regulation by the protein B. 11: PubMed Scopus Google Scholar). Rac in the to RhoGDI, which prevents dissociation and the Rac to interact with its guanine nucleotide GTP-loaded and to the plasma to interact with its the interaction Rac and is by protein-protein interactions and protein-lipid interactions I. R. 2000; Full Text Full Text PDF Scopus Google Scholar). The geranylgeranyl of Rac to a on RhoGDI, and lack of the modification prevents this interaction N. J. S. G. 2001; PubMed Scopus Google Scholar). We that statin of Rac isoprenylation disrupt the interaction with and for the GTP loading. We this by the interaction Rac and of statin was from and the resulting were with Statin treatment the of Rac with This result is of independent on the of Rac in with by at We used a to the effect statin-mediated of isoprenylation have on localization of an statin cellular from cells were and and for We observed that statin treatment the of Rac associated with the independent the reduction of Rac in the was levels of Rac were not because of of Rac in this The primary action of HMG-CoA reductase inhibitors is the inhibition of cholesterol which leads to reduction of plasma cholesterol levels (1Tobert J.A. Nat. Rev. Drug Discov. 2003; 2: 517-526Crossref PubMed Scopus (643) Google Scholar). these have been shown to have pleiotropic effects that are to cholesterol reduction (2Liao J.K. Laufs U. Annu. Rev. Pharmacol. Toxicol. 2004; 45: 89-118Crossref Scopus (1386) Google Scholar). Specifically, statins have been shown to have anti-inflammatory These effects have been to the of isoprenylation and the disruption of small G-protein functions (2Liao J.K. Laufs U. Annu. Rev. Pharmacol. Toxicol. 2004; 45: 89-118Crossref Scopus (1386) Google Scholar). Although the pleiotropic effects of statins have been demonstrated to of in the their mechanisms of action in the central nervous system are to be (2Liao J.K. Laufs U. Annu. Rev. Pharmacol. Toxicol. 2004; 45: 89-118Crossref Scopus (1386) Google Scholar, M. J. Atheroscler. Thromb. 2003; PubMed Scopus Google Scholar, U. H. C. S. M. G. 2002; PubMed Scopus Google Scholar). We and have reported the ability of statins to inflammatory in various models of central nervous system diseases including AD and multiple sclerosis (9Youssef S. Stuve O. Patarroyo J.C. Ruiz P.J. Radosevich J.L. Hur E.M. Bravo M. Mitchell D.J. Sobel R.A. Steinman L. Zamvil S.S. Nature. 2002; 420: 78-84Crossref PubMed Scopus (996) Google Scholar, A. Landreth G. J. Neurosci. 2005; 25: 299-307Crossref PubMed Scopus (156) Google Scholar, J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, N. S. R. I. J. Immunol. 2004; PubMed Scopus Google Scholar). epidemiological studies suggest that statin treatment reduces the risk of developing AD by (12Jick H. Zornberg G.L. Jick S.S. Seshadri S. Drachman D.A. Lancet. 2000; 356: 1627-1631Abstract Full Text Full Text PDF PubMed Scopus (1586) Google Scholar, 13Rockwood K. Kirkland S. Hogan D.B. MacKnight C. Merry H. Verreault R. Wolfson C. McDowell I. Arch. Neurol. 2002; 59: 223-227Crossref PubMed Scopus (476) Google Scholar, 14Wolozin B. Kellman W. Ruosseau P. Celesia G.G. Siegel G. Arch. Neurol. 2000; 57: 1439-1443Crossref PubMed Scopus (1343) Google however, a linkage be through clinical of the statins in AD recent studies have demonstrated statin-mediated in levels and in function D.L. Sabbagh M.N. Connor D.J. Lopez J. Launer L.J. Browne P. Wasser D. Johnson-Traver S. Lochhead J. Ziolwolski C. Arch. Neurol. 2005; 62: 753-757Crossref PubMed Scopus (384) Google Scholar, M. D. K. K. J. H. T. Neurol. 2002; PubMed Scopus Google Scholar, M. K. S. A. A. P. A. K. 2003; 16: PubMed Scopus Google Scholar, J.D. 2002; PubMed Google Scholar, J. M. J. 2004; PubMed Scopus Google Scholar). However, statins have been reported to increase the activation in M. J. Y. L. G. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). These results demonstrate the actions of these and the critical to their mechanisms of action. The AD is by the of by a microglia-mediated inflammatory response that and the primary disease H. S. S. B. J. P. M. S. H. M. Landreth G. L. R. J. G. C. J. R. Y. W. R. I. F.L. R. D. S. B. G. T. 2000; PubMed Scopus Google Scholar). Furthermore, cytokines have been shown to to the of the and the plaque with levels J.C. Landreth J. Neurosci. 2001; PubMed Google Scholar, D. 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Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google has demonstrated that the lack of isoprenylation prevents and translocation to the plasma in endothelial demonstrate a effect in microglia with to the is critical for activation of effectors including the NADPH oxidase, PAK, the and N. J. S. G. 2001; PubMed Scopus Google Scholar, L. C. 11: PubMed Scopus Google Scholar, Y. N. M. O. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). These an mechanism for the statin-mediated reduction in AD was that the actions were a consequence of reducing cholesterol levels with a inhibition of production J. B. T. R. M. S.S. 2001; PubMed Scopus Google Scholar, K. M. C. M. D. P. H. S. T. K. M. K. T. U. S. A. 2001; PubMed Scopus Google Scholar, S.S. S. N. A. T. K. M. J. Neurosci. 2002; PubMed Scopus Google Scholar, S. M. S. N. L. J.D. A. S. S. J. 2004; PubMed Scopus Google Scholar). of cholesterol from cellular decreases production of by the and the of S. J. Biol. 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