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J. Biol. Chem., Vol. 282, Issue 45, 32676-32688, November 9, 2007

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Involvement of Prostaglandin E₂ in Production of Amyloid- Peptides Both in Vitro and in Vivo^*

Tatsuya Hoshino, Tadashi Nakaya, Takashi Homan, Ken-ichiro Tanaka, Yukihiko Sugimoto^¶, Wataru Araki^||, Masami Narita^**, Shuh Narumiya, Toshiharu Suzuki, and Tohru Mizushima¹

From the Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan, the Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan, the ^¶Graduate School of Pharmaceutical Sciences and the Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan, the ^||National Institute of Neuroscience, Kodaira 187-8502, Japan, and the ^**Minase Research Institute, Ono Pharmaceutical Company, Limited, Osaka 618-8585, Japan

Amyloid- peptides (A), generated by proteolysis of the -amyloid precursor protein (APP) by - and -secretases, play an important role in the pathogenesis of Alzheimer disease (AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E₂ (PGE₂), a strong inducer of inflammation, stimulates the production of A in cultured human embryonic kidney (HEK) 293 or human neuroblastoma (SH-SY5Y) cells, both of which express a mutant type of APP. We have demonstrated using subtype-specific agonists that, of the four main subtypes of PGE₂ receptors (EP_1–4), EP₄ receptors alone or EP₂ and EP₄ receptors together are responsible for this PGE₂-stimulated production of A in HEK293 or SH-SY5Y cells, respectively. An EP₄ receptor antagonist suppressed the PGE₂-stimulated production of A in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels, and an analogue of cAMP stimulated the production of A, demonstrating that increases in the cellular level of cAMP are responsible for the PGE₂-stimulated production of A. Immunoblotting experiments and direct measurement of -secretase activity suggested that PGE₂-stimulated production of A is mediated by activation of-secretase but not of -secretase. Transgenic mice expressing the mutant type of APP showed lower levels of A in the brain, when they were crossed with mice lacking either EP₂ or EP₄ receptors, suggesting that PGE₂-mediated activation of EP₂ and EP₄ receptors is involved in the production of A in vivo and in the pathogenesis of AD.

Received for publication, April 12, 2007 , and in revised form, August 29, 2007.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Health, Labor, and Welfare of Japan, as well as the Japan Science and Technology Agency, and grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5 and additional references.

¹ To whom correspondence should be addressed: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. Tel./Fax: 81-96-371-4323; E-mail: mizu{at}gpo.kumamoto-u.ac.jp.

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				T. Hoshino, T. Namba, M. Takehara, T. Nakaya, Y. Sugimoto, W. Araki, S. Narumiya, T. Suzuki, and T. Mizushima Prostaglandin E2 Stimulates the Production of Amyloid-{beta} Peptides through Internalization of the EP4 Receptor J. Biol. Chem., July 3, 2009; 284(27): 18493 - 18502. [Abstract] [Full Text] [PDF]