Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease

Objective: There is significant evidence for a central role of inflammation in the development of Alzheimer disease (AD). Epidemiological studies indicate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD. Here, we investigate the function of prostaglandin E2 (PGE2) signaling through its EP3 receptor in the neuroinflammatory response to A beta peptide. Methods: The function of PGE2 signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of A beta 42 peptides. Our findings were then confirmed in young adult APPSwe-PS1?E9 transgenic mice. Results: Deletion of the PGE2 EP3 receptor in a model of A beta 42 peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1?E9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of A beta peptides were significantly decreased, as were beta-secretase and beta C-terminal fragment levels, suggesting that generation of A beta peptides may be increased as a result of proinflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in presynaptic proteins seen in APPSwe-PS1?E9 mice. Interpretation: Our findings identify the PGE2 EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE2-EP3 signaling in the development of AD. ANN NEUROL 2012;72:788798