ALTERED LIPID MEDIATORS AND RECEPTORS OF RESOLUTION IN THE ENTORHINAL CORTEX OF ALZHEIMER'S DISEASE

Abstract

Alzheimer’ disease pathogenesis. Primary murine microglia that lack prostaglandin E 2 receptor subtype 2 (EP2) have a dual phenotype of decreased innate immune-mediated neurotoxicity and increased Ab peptide phagocytosis, features that have been replicated in vivo. Here we tested the hypothesis that expression and activity of scavenger receptor CD36 influences EP2-regulated A b phagocytosis. Methods: Primary microglia were isolated from brains of newborn C57BL/6 mice. CD36 mRNA and protein levels were assessed by quantitative real-time PCR and flow cytometry, respectively.Ab 42 phagocytosis by primary microglia was determined by incubation with pHrodo-labeled Ab 42 followed by flow cytometry. CD36 mRNA levels were measured in hippocampus of mice following intracerebroventricular (ICV) injection of PIC, TLR3 activator. Results: Treatment of microglia with the EP2 agonist Butaprost reduced CD36 expression, as measured by mRNA and cell surface protein levels, and inhibited microglial A b 42 phagocytosis. Consistent with these findings, preventing EP2 activation by both pharmacological and genetic approaches increased microglial CD36 expression as well as A b 42 phagocytosis. Activation of the innate immune response by TLR activators, such as TLR3, TLR4 and TLR7, similarly reduced CD36 expression and phagocytic capacity in primary microglia. These effects were reduced by at least half by an EP2 antagonist, AH 6809, with the microglia Ab 42 phagocytosis effect completely dependent on CD36 activity. Finally, our in vivo studies demonstrated that hippocampal CD36 mRNA levels were significantly reduced following ICV injection of theTLR3 activator PIC; this effect was reversed by an EP2 antagonist. Conclusions: Our results are consistent with those of other studies in supporting a key role for CD36 in Ab phagocytosis by microglia and highlight selective EP2 antagonists as an effective means to suppress this toxic reinforcing cycle. Our findings suggest that EP2 antagonists have potential as a therapeutic approach to suppressing key aspects of AD pathogenesis.