3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Abstract

Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar ␤-amyloid (A␤) in the brain, a fulminant microglialmediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the A␤-stimulated expression of interleukin-1␤ and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal A␤ production and microglia-directed inflammation.

Atorvastatin prevents amyloid-β peptide oligomer-induced synaptotoxicity and memory dysfunction in rats through a p38 MAPK-dependent pathway

“…The proposed mechanisms by which statins may act include a reduction in brain Aβ production through alterations in metabolism of amyloid precursor protein [46] and a reduction in inflammation attributable to microglia activation [45] . In vitro experiments have shown that statins attenuate inflammatory responses mediated by Aβ peptides [47] . In vivo statin use has also resulted in robust anti-inflammatory effects [48] .…”

Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death

“…Recently, our laboratory and that of others have reported that neuroprotective efficacies of statins are mediated by their anti-inflammatory activity under various neurological disease conditions such as human multiple sclerosis [38] and its animal models [20,23,[33][34][35], Spinal cord injury [24], X-linked adrenoleukodystrophy [22], Alzheimer's disease [6], traumatic brain injury [39], and stroke [12]. In these studies, statins inhibited inflammatory signal cascades and gene expression through inhibition of isoprenylation of small GTPase (Ras and RhoA) [21,24,26].…”

Statins and Brain Dysfunction

“…38 Statins have been shown to reduce the production of iNOS from activated microglial cells and macrophages. 39,40 Additionally, lovastatin was also shown to signifi cantly reduce prostaglandin E2 release from microglia, either under basal conditions or after stimulation by IL-1B, in primary cultures of rat cortical microglia. 41 Statins have also been shown in rats and human microglia to reduce the production of the proinfl ammatory cytokine IL-6.…”