title: Simvastatin inhibits protein isoprenylation in the brain.
abstract: Evidence suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, may reduce the risk of Alzheimer's disease (AD). Statin action in patients with AD, as in those with heart disease, is likely to be at least partly independent of the effects of statins on cholesterol. Statins can alter cellular signaling and protein trafficking through inhibition of isoprenylation of Rho, Cdc42, and Rab family GTPases. The effects of statins on protein isoprenylation in vivo, particularly in the central nervous system, are poorly studied. We utilized two-dimensional gel electrophoresis approaches to directly monitor the levels of isoprenylated and non-isoprenylated forms of Rho and Rab family GTPases. We report that simvastatin significantly inhibits RhoA and Rab4, and Rab6 isoprenylation at doses as low as 50nM in vitro. We also provide the first in vivo evidence that statins inhibit the isoprenylation of RhoA in the brains of rats and RhoA, Cdc42, and H-Ras in the brains of mice treated with clinically relevant doses of simvastatin.
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ostrowski
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Kachael
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Siefert
authors.affiliation: Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Sam
authors.initials: S
authors.lastname: Shank
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, and Centro Cardiologico Monzino, Milan, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
authors.affiliation: Departments of Pharmacology and Neurology, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. Electronic address: assem.ziady@cchmc.org.
authors.forename: Assem G
authors.initials: AG
authors.lastname: Ziady
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002491:Central Nervous System Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D015180:Electrophoresis, Gel, Two-Dimensional; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007525:Isoelectric Focusing; D008810:Mice, Inbred C57BL; D017368:Protein Prenylation / Q000187:drug effects*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011918:Rats, Inbred SHR; D019821:Simvastatin / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: C581598:Cdc42 protein, mouse; D002491:Central Nervous System Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: Alzheimer’s disease; Cdc42; Rab; RhoA; isoprenylation; simvastatin