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.[1]References
- Microglia lacking E Prostanoid Receptor subtype 2 have enhanced Abeta phagocytosis yet lack Abeta-activated neurotoxicity. Shie, F.S., Breyer, R.M., Montine, T.J. Am. J. Pathol. (2005) [Pubmed]
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