title: Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP(4)  receptor.
abstract: Amyloid-β peptide (Aβ), which is generated by the β- and γ-secretase-mediated proteolysis of β-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E(2) (PGE(2) ) stimulates the production of Aβ through both EP(2) and EP(4) receptors and that activation of the EP(4) receptor stimulates Aβ production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP(2) or EP(4) receptors, respectively. Mice lacking the EP(4) receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP(4) receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aβ and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP(4) receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP(4) receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.
authors: Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors: Tatsuya
authors: T
authors: Hoshino
authors: Takushi
authors: T
authors: Namba
authors: Masaya
authors: M
authors: Takehara
authors: Naoya
authors: N
authors: Murao
authors: Takahide
authors: T
authors: Matsushima
authors: Yukihiko
authors: Y
authors: Sugimoto
authors: Shuh
authors: S
authors: Narumiya
authors: Toshiharu
authors: T
authors: Suzuki
authors: Tohru
authors: T
authors: Mizushima
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications* / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009281:Naphthalenes / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010654:Phenylbutyrates; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D000090802:rab7 GTP-Binding Proteins; D053829:Amyloid Precursor Protein Secretases; D020691:rab GTP-Binding Proteins