Prostaglandin E2 Stimulates the Production of Amyloid-β Peptides through Internalization of the EP4 Receptor

Amyloid-beta (A beta) peptides, generated by the proteolysis of beta-amyloid precursor protein by beta- and gamma-secretases, play an important role in the pathogenesis of Alzheimer disease. Inflammation is also important. We recently reported that prostaglandin E-2 (PGE(2)), a strong inducer of inflammation, stimulates the production of A beta through EP2 and EP4 receptors, and here we have examined the molecular mechanism. Activation of EP2 and EP4 receptors is coupled to an increase in cellular cAMP levels and activation of protein kinase A (PKA). We found that inhibitors of adenylate cyclase and PKA suppress EP2, but not EP4, receptor-mediated stimulation of the A beta production. In contrast, inhibitors of endocytosis suppressed EP4, but not EP2, receptor-mediated stimulation. Activation of gamma-secretase was observed with the activation of EP4 receptors but not EP2 receptors. PGE(2)-dependent internalization of the EP4 receptor was observed, and cells expressing a mutant EP4 receptor lacking the internalization activity did not exhibit PGE(2)-stimulated production of A beta. A physical interaction between the EP4 receptor and PS-1, a catalytic subunit of gamma-secretases, was revealed by immunoprecipitation assays. PGE(2)-induced internalization of PS-1 and co-localization of EP4, PS-1, and Rab7 (a marker of late endosomes and lysosomes) was observed. Co-localization of PS-1 and Rab7 was also observed in the brain of wild-type mice but not of EP4 receptor null mice. These results suggest that PGE(2)-stimulated production of A beta involves EP4 receptor-mediated endocytosis of PS-1 followed by activation of the gamma-secretase, as well as EP2 receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease.