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-␣. 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.High levels of cholesterol, and in particular of cholesterol esters (1), influence the generation and aggregation of ␤-amyloid peptides in dissociated cell cultures (2-6) and transgenic mice (7). Patients with high plasma cholesterol levels and cardiovascular diseases have increased risk of Alzheimer's disease (AD) 1 (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). These observations have led to an extensive and ongoing evaluation of statins as preventive treatments for Alzheimer's disease (13-16).Mevalonate, a cholesterol precursor, the synthesis of which is blocked by statins, is converted into several bioactive compounds. Among these, the isoprenoids are of particular importance because, among other functions, they provide for the covalent addition of lipid moieties (prenylation) to regulatory proteins (17) and thereby affect critical cell functions. Prenylation by the mevalonate products farnesyl diphosphate and geranylgeranyl diphosphate, ...

Mechanisms of Statin-mediated Inhibition of Small G-protein Function

“…In addition, recent prospective studies have demonstrated statin-mediated reductions in soluble A␤ levels and improvements in cognitive function (15,(35)(36)(37)(38). However, recently statins have been reported to increase the microglial activation in hippocampal slice cultures (39). These results demonstrate the complex were treated with increasing concentrations of simvastatin or lovastatin for 18 h. Cells were lysed, and GTP-loaded Rac was isolated with PAK-GST beads.…”

Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer Disease

“…Using statin-treated hippocampal slice preparations, one study showed that inhibition of protein geranylgeranylation elicited microglial activation (41). Conversely, another study demonstrated that statin-induced inhibition of protein geranylgeranylation suppressed the A␤-stimulated inflammation in microglial cultures (18).…”

A Pivotal Role for Interleukin-4 in Atorvastatin-associated Neuroprotection in Rat Brain

“…On the one hand certain statins have been reported to induce inflammation, for instance lovastatin has been shown to increase IL-1␤ concentration in brain tissue of transgenic mice, which overexpress human amyloid precursor protein (30), and TNF␣ concentration in cultured hippocampal slices (13). Similarly, cerivastatin and fluvastatin have been reported to up-regulate IL-1␤-and IFN␥-induced changes in smooth muscle (31,32) and hepatoma cells (32).…”

“…statins) that are distinct from their ability to lower cholesterol. It has been shown that statins reduce A␤ deposition and inflammatory changes in mouse models of Alzheimer disease (12)(13)(14), block paralysis in chronic and relapsing experimental autoimmune encephalomyelitis (15), reduce infarct size in ischemia, and improve neurologic outcome by directly up-regulating brain endothelial nitric-oxide synthase (16). Statins have also been shown to decrease symptoms and mortality in stroke-prone spontaneously hypertensive rats (17).…”