Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity.
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.
Shie
Feng-Shiun
FS
Department of Pathology, University of Washington, Box 359645, Harborview Medical Center, 325 9th Ave., Seattle, WA 98104, USA. fshie@u.washington.edu
Breyer
Richard M
RM
Montine
Thomas J
TJ
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D002478:Cells, Cultured; D054407:Chemokine CCL4; D002630:Chemotactic Factors / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000172:deficiency*
D016229:Amyloid beta-Peptides; D054407:Chemokine CCL4; D002630:Chemotactic Factors; D019402:Macrophage Inflammatory Proteins; D018078:Receptors, Prostaglandin E; D011493:Protein Kinase C