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

Abstract

Amyloid-␤ (A␤) peptides, generated by the proteolysis of ␤-amyloid precursor protein by ␤-and ␥-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␤ through EP 2 and EP 4 receptors, and here we have examined the molecular mechanism. Activation of EP 2 and EP 4 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 EP 2 , but not EP 4 , receptor-mediated stimulation of the A␤ production. In contrast, inhibitors of endocytosis suppressed EP 4 , but not EP 2 , receptor-mediated stimulation. Activation of ␥-secretase was observed with the activation of EP 4 receptors but not EP 2 receptors. PGE 2 -dependent internalization of the EP 4 receptor was observed, and cells expressing a mutant EP 4 receptor lacking the internalization activity did not exhibit PGE 2 -stimulated production of A␤. A physical interaction between the EP 4 receptor and PS-1, a catalytic subunit of ␥-secretases, was revealed by immunoprecipitation assays. PGE 2 -induced internalization of PS-1 and co-localization of EP 4 , 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 EP 4 receptor null mice. These results suggest that PGE 2 -stimulated production of A␤ involves EP 4 receptor-mediated endocytosis of PS-1 followed by activation of the ␥-secretase, as well as EP 2 receptor-dependent activation of adenylate cyclase and PKA, both of which are important in the inflammation-mediated progression of Alzheimer disease. Alzheimer disease (AD)2 is the most common neurodegenerative disorder of the central nervous system and the leading cause of adult onset dementia. AD is characterized pathologically by the accumulation of tangles and senile plaques. Senile plaques are composed of the amyloid-␤ (A␤) peptides A␤40 and A␤42 (1, 2). To generate A␤, ␤-amyloid precursor protein (APP) is first cleaved by ␤-secretase and then by ␥-secretase. Cleavage of APP by ␣-secretase produces non-amyloidogenic peptides (3, 4). The ␥-secretase is an aspartyl protease complex composed of four core components, including presenilin (PS) 1 and PS2 (5). Early onset familial AD is linked to three genes, APP, PS1, and PS2 (5, 6), strongly suggesting that ␥-secretasedependent production of A␤ is a key factor in the pathogenesis of AD. Therefore, cellular factors that affect the ␥-secretase-dependent production of A␤ may be good targets for the development of drugs to prevent and treat AD.Both APP and PS-1 are transmembrane proteins, and their intracellular localization is controlled by secretory and endocytic pathways. These proteins are modified in the endoplasmic reticulum and trafficked to the cell surface through the transGolgi network (TGN). Then, they are internalized again and traf...

Analysis of genes causing hypertension and stroke in spontaneously hypertensive rats: Gene expression profiles in the brain

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Suppression of Alzheimer's Disease-Related Phenotypes by Expression of Heat Shock Protein 70 in Mice

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