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.
Highlights
High levels of cholesterol, and in particular of cholesterol esters [1], influence the generation and aggregation of -amyloid peptides in dissociated cell cultures [2,3,4,5,6] and transgenic mice [7]
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 Alzheimer’s disease (AD) with uncertain relationships to other features of the disease
Our results indicate that statins elicit microglial activation, as evidenced by transformation to macrophage morphology and up-regulation of the cytokine TNF-␣, and that this effect is likely due to suppression of the mevalonate pathway and of its geranylgeranyl products
Summary
In particular of cholesterol esters [1], influence the generation and aggregation of -amyloid peptides in dissociated cell cultures [2,3,4,5,6] and transgenic mice [7]. Diovascular diseases have increased risk of Alzheimer’s disease (AD) (8 –10), and there is evidence that statins, a family of compounds that inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A reductase: HMG-CoA reductase), decrease the incidence of the disease [11, 12]. Whether statins influence the activation of microglia, the resident cells mediating inflammatory responses in brain, is unknown, the question is of evident importance for the use of the drugs in AD. The present study explored the effects of inhibiting HMGCoA reductase on microglial morphology and expression of the cytokine TNF-␣ using a novel cultured brain slice preparation. This preparation has been used previously to study pathologies
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