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Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia.

Abstract
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-alpha. 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-alpha 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.
AuthorsXiaoning Bi, Michel Baudry, Jihua Liu, Yueqin Yao, Lawrence Fu, Fernando Brucher, Gary Lynch
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 46 Pg. 48238-45 (Nov 12 2004) ISSN: 0021-9258 [Print] United States
PMID15364922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, CD11b
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Polyisoprenyl Phosphates
  • Terpenes
  • Tumor Necrosis Factor-alpha
  • mevastatin
  • geranylgeranyl pyrophosphate
  • Lovastatin
  • Simvastatin
  • Extracellular Signal-Regulated MAP Kinases
  • rho GTP-Binding Proteins
  • Mevalonic Acid
Topics
  • Alzheimer Disease (drug therapy, metabolism)
  • Animals
  • Antigens, CD11b (metabolism)
  • Cell Proliferation
  • Cell Shape
  • Dose-Response Relationship, Drug
  • Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
  • Hippocampus (cytology, metabolism)
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
  • In Vitro Techniques
  • Lovastatin (analogs & derivatives, pharmacology)
  • Mevalonic Acid (metabolism)
  • Microglia (cytology, drug effects, immunology, metabolism)
  • Polyisoprenyl Phosphates (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Simvastatin (pharmacology)
  • Terpenes (metabolism)
  • Tumor Necrosis Factor-alpha (metabolism)
  • rho GTP-Binding Proteins (metabolism)

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