INVOLVEMENT OF PROSTAGLANDIN E_2 IN PRODUCTION OF AMYLOID-b PEPTIDES BOTH IN VITRO AND IN VIVO

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Amyloid-β peptides (Aβ., generated by proteolysis of the βamyloid precursor protein (APP) by β- and γ-secretases, play an important role in the pathogenesis of Alzheimer's disease (AD). Inflammation is also believed to be integral to the pathogenesis of AD. Here we show that prostaglandin E_2 (PGE_2), a strong inducer of inflammation, stimulates the production of Aβ 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 PGE_2 receptors (EP_<1-4>), EP_4 receptors alone or EP_2 and EP_4 receptors together are responsible for this PGE_2-stimulated production of Aβ in HEK293 or SH-SY5Y cells, respectively. An EP_4 receptor antagonist suppressed the PGE_2-stimulated production of Aβ in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels and an analogue of cAMP stimulated the production of Aβ, demonstrating that an increases in the cellular level of cAMP are responsible for the PGE_2-stimulated production of Aβ. Immunoblotting experiments and direct measurement of γsecretase activity suggested that PGE_2-stimulated production of Aβ is mediated by activation of γ-secretase but not of β-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of Aβ in the brain, when they were crossed with mice lacking either EP_2 or EP_4 receptors, suggesting that PGE_2-mediated activation of EP_2 and EP_4 receptors is involved in the production of Aβ in vivo and in the pathogenesis of AD.