Prostaglandin E2 stimulates the production of amyloid-beta peptides through internalization of the EP4 receptor.
Amyloid-beta (Abeta) 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 Abeta 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 Abeta production. In contrast, inhibitors of endocytosis suppressed EP(4), but not EP(2), receptor-mediated stimulation. Activation of gamma-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 Abeta. A physical interaction between the EP(4) 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 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 Abeta involves EP(4) receptor-mediated endocytosis of PS-1 followed by activation of the gamma-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.
Hoshino
Tatsuya
T
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Namba
Takushi
T
Takehara
Masaya
M
Nakaya
Tadashi
T
Sugimoto
Yukihiko
Y
Araki
Wataru
W
Narumiya
Shuh
S
Suzuki
Toshiharu
T
Mizushima
Tohru
T
D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002966:Clathrin / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D016229:Amyloid beta-Peptides; D002966:Clathrin; C545650:PTGER4 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C545651:Ptger4 protein, mouse; D034741:RNA, Small Interfering; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D049452:Green Fluorescent Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D020691:rab GTP-Binding Proteins; D000262:Adenylyl Cyclases; D015232:Dinoprostone