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

Autor: Lawrence Fu, Xiaoning Bi, Jihua Liu, Fernando A. Brucher, Michel Baudry, Gary Lynch, Yueqin Yao
Rok vydání: 2004
Předmět:
rho GTP-Binding Proteins
Simvastatin
medicine.medical_specialty
Statin
Geranylgeranyl pyrophosphate
medicine.drug_class
Mevalonic Acid
In Vitro Techniques
Hippocampus
Biochemistry
Rats
Sprague-Dawley
chemistry.chemical_compound
Geranylgeranylation
Mevastatin
Polyisoprenyl Phosphates
Prenylation
Alzheimer Disease
Internal medicine
medicine
Animals
Lovastatin
Extracellular Signal-Regulated MAP Kinases
Cell Shape
Molecular Biology
Cell Proliferation
CD11b Antigen
Dose-Response Relationship
Drug
biology
Microglia
Terpenes
Tumor Necrosis Factor-alpha
Cell Biology
Rats
Cell biology
Endocrinology
medicine.anatomical_structure
chemistry
HMG-CoA reductase
biology.protein
lipids (amino acids
peptides
and proteins)
Tumor necrosis factor alpha
Hydroxymethylglutaryl-CoA Reductase Inhibitors
medicine.drug
Zdroj: Journal of Biological Chemistry. 279:48238-48245
ISSN: 0021-9258
DOI: 10.1074/jbc.m405442200
Popis: 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.
Databáze: OpenAIRE
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