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Improvement of cognitive function in Alzheimer’s disease model mice by genetic and pharmacological inhibition of the EP 4 receptor
Author(s) -
Hoshino Tatsuya,
Namba Takushi,
Takehara Masaya,
Murao Naoya,
Matsushima Takahide,
Sugimoto Yukihiko,
Narumiya Shuh,
Suzuki Toshiharu,
Mizushima Tohru
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07567.x
Subject(s) - receptor , genetically modified mouse , endocrinology , amyloid precursor protein , alzheimer's disease , medicine , receptor antagonist , transgene , endocytosis , chemistry , biology , antagonist , pharmacology , biochemistry , disease , gene
J. Neurochem. (2012) 120 , 795–805. 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.