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J. Biol. Chem., Vol. 279, Issue 46, 48238-48245, November 12, 2004

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Inhibition of Geranylgeranylation Mediates the Effects of 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors on Microglia^*

Xiaoning Bi, Michel Baudry¶, Jihua Liu, Yueqin Yao, Lawrence Fu, Fernando Brucher, and Gary Lynch

From the Department of Psychiatry & Human Behavior, University of California Irvine, Irvine, CA 92617-1695 and the ^¶Neurobiology Program, Biological Science, University of Southern California, Los Angeles, CA 90089

Inflammatory responses involving microglia, the resident macrophages of the brain, are thought to contribute importantly to the progression of Alzheimer's disease (AD) and possibly other neurodegenerative disorders. The present study tested whether the mevalonate-isoprenoid biosynthesis pathway, which affects inflammation in many types of tissues, tonically regulates microglial activation. This question takes on added significance given the potential use of statins, drugs that block the rate-limiting step (3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase)) in mevalonate and cholesterol synthesis, in AD treatment. Both mevastatin and simvastatin caused a concentration- and time-dependent activation of microglia in cultured rat hippocampal slices. This response consisted of a transformation of the cells from a typical resting configuration to an amoeboid, macrophage-like morphology, increased expression of a macrophage antigen, and up-regulation of the cytokine tumor necrosis factor-. Evidence for proliferation was also obtained. Statin-induced microglial changes were blocked by mevalonate but not by cholesterol, indicating that they were probably due to suppression of isoprenoid synthesis. In accord with this, the statin effects were absent in slices co-incubated with geranylgeranyl pyrophosphate, a mevalonate product that provides for the prenylation of Rho GTPases. Finally, PD98089, a compound that blocks activation of extracellularly regulated kinases1/2, suppressed statin-induced up-regulation of tumor necrosis factor- but had little effect on microglial transformation. These results suggest that 1) the mevalonate-isoprenoid pathway is involved in regulating microglial morphology and in controlling expression of certain cytokines and 2) statins have the potential for enhancing a component of AD with uncertain relationships to other features of the disease.

Received for publication, May 17, 2004 , and in revised form, August 12, 2004.

^* This study was supported by grants from the NIA National Institutes of Health (Grant AG-00538), The Thuris Corp., and UC BioSTAR. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: 101 Theory Dr., Number 250, University of California, Irvine, CA 92617-1695. Tel.: 949-824-4393; Fax: 949-824-3559; E-mail: xbi{at}uci.edu.

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