Abstract
Recent studies have shown that the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) possess antiinflammatory and immunomodulatory properties, distinct from their action of lowering serum lipid levels. Moreover, results of epidemiological studies suggest that long‐term use of statins is associated with a decreased risk for Alzheimer's disease (AD). Interestingly, lovastatin (one of the most commonly used anticholesterol drugs) treatment of vascular‐derived cells has been reported to antagonize activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, and it is well known that the JAK/STAT pathway plays a central role in interferon‐γ (IFN‐γ)‐induced microglial CD40 expression. We and others have previously reported that microglial CD40 expression is significantly induced by IFN‐γ and amyloid‐β (Aβ) peptide. Moreover, it has been shown that CD40 signaling is critically involved in microglia‐related immune responses in the CNS. In this study, we examined the putative role of lovastatin in modulation of CD40 expression and its signaling in cultured microglia. RT‐PCR, Western immunoblotting, and flow cytometry data show that lovastatin suppresses IFN‐γ‐induced CD40 expression. Additionally, lovastatin markedly inhibits IFN‐γ‐induced phosphorylation of JAK/STAT1. Furthermore, lovastatin is able to suppress microglial tumor necrosis factor‐α, interleukin (IL)‐β1 and IL‐6 production promoted either by IFN‐γ or by Aβ peptide challenge in the presence of CD40 cross‐linking. To characterize further lovastatin's effect on microglial function, we examined microglial phagocytic capability following CD40 cross‐linking. Data reveal that lovastatin markedly attenuates CD40‐mediated inhibition of microglial phagocytosis of Aβ. These results provide an insight into the mechanism of the beneficial effects of lovastatin in neurodegenerative disorders, particularly Alzheimer's disease. © 2004 Wiley‐Liss, Inc.