Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity.

Shie FS, Breyer RM, Montine TJ
Am J Pathol. 2005 166 (4): 1163-72

PMID: 15793296 · PMCID: PMC1602400 · DOI:10.1016/s0002-9440(10)62336-x

Experimental therapies for Alzheimer's disease (AD) are focused on enhanced clearance of neurotoxic Abeta peptides from brain. Microglia can be neuroprotective by phagocytosing Abeta; however, this comes at the cost of activated innate immunity that causes paracrine damage to neurons. Here, we show that ablation of E prostanoid receptor subtype 2 (EP2) significantly increased microglial-mediated clearance of Abeta peptides from AD brain sections and enhanced microglial Abeta phagocytosis in cell culture. The enhanced phagocytosis was PKC-dependent and was associated with elevated microglial secretion of the chemoattractant chemokines, macrophage inflammatory protein-1alpha and macrophage chemoattractant protein-1. This suggested that microglial activation is negatively regulated by EP2 signaling through suppression of prophagocytic cytokine secretion. However, despite this enhancement of Abeta phagocytosis, lack of EP2 completely suppressed Abeta-activated microglia-mediated paracrine neurotoxicity. These data demonstrate that blockade of microglial EP2 is a highly desirable mechanism for AD therapy that can maximize neuroprotective actions while minimizing bystander damage to neurons.

MeSH Terms (15)

Amyloid beta-Peptides Animals Cell Count Cells, Cultured Chemokine CCL4 Chemotactic Factors Hippocampus Macrophage Inflammatory Proteins Macrophages Mice Microglia Neurons Phagocytosis Protein Kinase C Receptors, Prostaglandin E

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