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• W2036769045 abstract "Inflammation is a driving force in Alzheimer's disease (AD) pathology; strategies targeting the brain inflammatory response may thus be effective for prevention or therapy. Epidemiological studies report a reduced risk for AD among normal aging populations who chronically use non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit the production of prostaglandins. However, detrimental effects of chronic NSAID use suggest that prostaglandins mediate other beneficial roles. In accordance with this, we recently identified the prostaglandin E2 (PGE2) E prostanoid 4 (EP4) receptor as a potent anti-inflammatory mediator in microglia. In this study, we investigated the cell-specific function of microglial EP4 in the brain immune response to amyloid-ß (Aß). To examine EP4 signaling in vitro, we cultured BV2 cells and primary murine microglia and assessed the response to Aß and to co-treatment with an EP4 specific agonist. Quantitative RT-PCR and ELISA from cell supernatants were used to determine the RNA and protein levels of inflammatory factors. To extend our studies in vivo, we used the Cre-LoxP genetic strategy with the CD11b promoter to generate APPswe-PS1-E9 mice specifically lacking EP4 in microglia. From these mice, we obtained hippocampal samples for quantitative RT-PCR analysis, cortical tissue for Aß ELISA, and tissue sections for immunohistochemistry and Congo Red amyloid plaque analysis. We find that EP4 drives an anti-inflammatory response in microglia by inhibiting pro-inflammatory and pro-amyloidogenic pathways. In primary microglia and BV2 cells, EP4 stimulation reduced the expression and secretion of pro-inflammatory cytokines and chemokines in response to Aß. In vivo, conditional deletion of EP4 in microglia increased pro-inflammatory gene expression in the brains of APPswe-PS1-E9 AD model mice. This inflammatory response was associated with significantly elevated plaque deposition in the hippocampus and increased Aß levels in the cortex, indicating accelerated disease pathology when EP4 is absent in microglia. Our study highlights the potential of cell-specific genetic strategies to identify therapeutic targets in animal models of AD. Specifically, these findings identify the microglial EP4 receptor as a novel anti-inflammatory and anti-amyloidogenic pathway in a mouse model of AD. Strategies targeting microglial EP4 signaling may thus prove an effective direction for the prevention or treatment of AD." @default.
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• W2036769045 date "2011-07-01" @default.
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• W2036769045 title "P4-287: Prostaglandin E2 E-prostanoid 4 receptor signaling in microglia reduces inflammation and amyloid burden in a mouse model of Alzheimer's disease" @default.
• W2036769045 doi "https://doi.org/10.1016/j.jalz.2011.09.032" @default.
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