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(American Journal of Pathology. 2005;166:1163-1172.)
© 2005 American Society for Investigative Pathology

Microglia Lacking E Prostanoid Receptor Subtype 2 Have Enhanced Aß Phagocytosis yet Lack Aß-Activated Neurotoxicity

Feng-Shiun Shie^*, Richard M. Breyer and Thomas J. Montine^*

From the Department of Pathology,^* University of Washington, Seattle, Washington; and the Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee

Experimental therapies for Alzheimer’s disease (AD) are focused on enhanced clearance of neurotoxic Aß peptides from brain. Microglia can be neuroprotective by phagocytosing Aß; 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 Aß peptides from AD brain sections and enhanced microglial Aß phagocytosis in cell culture. The enhanced phagocytosis was PKC-dependent and was associated with elevated microglial secretion of the chemoattractant chemokines, macrophage inflammatory protein-1 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 Aß phagocytosis, lack of EP2 completely suppressed Aß-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.

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