RRC ID 37697
Author Hoshino T, Namba T, Takehara M, Nakaya T, Sugimoto Y, Araki W, Narumiya S, Suzuki T, Mizushima T.
Title Prostaglandin E2 stimulates the production of amyloid-beta peptides through internalization of the EP4 receptor.
Journal J. Biol. Chem.
Abstract 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.
Volume 284(27)
Pages 18493-502
Published 2009-7-3
DOI 10.1074/jbc.M109.003269
PII M109.003269
PMID 19407341
PMC PMC2709369
MeSH Adenylyl Cyclases / metabolism Alzheimer Disease / metabolism* Amyloid Precursor Protein Secretases / metabolism Amyloid beta-Peptides / metabolism* Animals CHO Cells Clathrin / genetics Clathrin / metabolism Cricetinae Cricetulus Cyclic AMP-Dependent Protein Kinases / metabolism Dinoprostone / metabolism* Dinoprostone / pharmacology Endocytosis / drug effects Endocytosis / physiology* Green Fluorescent Proteins / genetics Humans Kidney / cytology Mice Mice, Transgenic Peptide Fragments / metabolism Presenilin-1 / metabolism RNA, Small Interfering Receptors, Prostaglandin E / metabolism* Receptors, Prostaglandin E, EP4 Subtype Transfection rab GTP-Binding Proteins / metabolism
IF 4.106
Times Cited 37
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
Human and Animal Cells