Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease.

Shi J, Wang Q, Johansson JU, Liang X, Woodling NS, Priyam P, Loui TM, Merchant M, Breyer RM, Montine TJ, Andreasson K
Ann Neurol. 2012 72 (5): 788-98

PMID: 22915243 · PMCID: PMC3509238 · DOI:10.1002/ana.23677

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 E(2) (PGE(2) ) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide.

METHODS - The function of PGE(2) signaling through its EP3 receptor was examined in vivo in a model of subacute neuroinflammation induced by administration of Aβ(42) peptides. Our findings were then confirmed in young adult APPSwe-PS1ΔE9 transgenic mice.

RESULTS - Deletion of the PGE(2) EP3 receptor in a model of Aβ(42) peptide-induced neuroinflammation reduced proinflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1ΔE9 model of familial AD, deletion of the EP3 receptor blocked induction of proinflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were β-secretase and β C-terminal fragment levels, suggesting that generation of Aβ 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-PS1ΔE9 mice.

INTERPRETATION - Our findings identify the PGE(2) EP3 receptor as a novel proinflammatory, proamyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE(2) -EP3 signaling in the development of AD.

Copyright © 2012 American Neurological Association.

MeSH Terms (37)

Age Factors Alzheimer Disease Amyloid beta-Peptides Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Analysis of Variance Animals Animals, Newborn Aspartic Acid Endopeptidases Brain Calcium-Binding Proteins Cells, Cultured Cognitive Dysfunction Dinoprostone Disease Models, Animal DNA-Binding Proteins Encephalitis Female Gene Expression Regulation Glial Fibrillary Acidic Protein Humans Male Mice Mice, Inbred C57BL Mice, Transgenic Microfilament Proteins Microtubule-Associated Proteins Mutation Neurons Oxidative Stress Peptide Fragments Prostaglandin-Endoperoxide Synthases Receptors, Prostaglandin E, EP3 Subtype RNA, Messenger Signal Transduction Synaptosomal-Associated Protein 25 Vesicle-Associated Membrane Protein 2

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