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.