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M405442200v1
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Papers In Press, published online ahead of print September 9, 2004
J. Biol. Chem, 10.1074/jbc.M405442200
Submitted on May 17, 2004
Revised on September 9, 2004
Accepted on September 9, 2004

Inhibition of geranylgeranylation mediates the effects of HMG-CoA reductase inhibitors on microglia

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

Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA 92612

Corresponding Author: xbi{at}uci.edu

Inflammatory responses involving microglia, the brain’s resident macrophages, are thought to contribute importantly to the progression of Alzheimer’s disease (AD) and possibly other neurodegenerative disorders. The present study tested if 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 (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 upregulation of the cytokine tumor necrosis factor-alpha (TNF-a_. 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 upregulation of TNF-a, 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.


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