Format

Send to

Choose Destination
Neuroscience. 2016 Aug 4;329:264-74. doi: 10.1016/j.neuroscience.2016.04.053. Epub 2016 May 12.

Simvastatin inhibits protein isoprenylation in the brain.

Author information

1
Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
2
Department of Pediatrics, Emory University, Atlanta, GA, USA; Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
3
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
4
Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
5
Department of Pharmacological and Biomolecular Sciences, University of Milan, and Centro Cardiologico Monzino, Milan, Italy.
6
Departments of Pharmacology and Neurology, Boston University School of Medicine, Boston, MA, USA.
7
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.

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.

KEYWORDS:

Alzheimer’s disease; Cdc42; Rab; RhoA; isoprenylation; simvastatin

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center