Involvement of prostaglandin E₂ in production of amyloid-β peptides both in vitro and in vivo

Amyloid-β peptides (Aβ), generated by proteolysis of the β-amyloid precursor protein (APP) by β- and γ-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 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 PGE₂ receptors (EP_1-4), EP₄ receptors alone or EP₂ and EP₄ receptors together are responsible for this PGE₂-stimulated production of Aβ in HEK293 or SH-SY5Y cells, respectively. An EP₄ receptor antagonist suppressed the PGE₂-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 increases in the cellular level of cAMP are responsible for the PGE ₂-stimulated production of Aβ. Immunoblotting experiments and direct measurement of γ-secretase 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 EP₂ or EP₄ receptors, suggesting that PGE₂-mediated activation of EP₂ and EP₄ receptors is involved in the production of Aβ in vivo and in the pathogenesis of AD.