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

Amyloid-beta peptides (A beta), generated by proteolysis of the beta- amyloid precursor protein ( APP) by beta- and gamma-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 E-2 (PGE(2)), a strong inducer of inflammation, stimulates the production of A beta 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 (EP1-4), EP4 receptors alone or EP2 and EP4 receptors together are responsible for this PGE(2)- stimulated production of A beta in HEK293 or SH-SY5Y cells, respectively. An EP4 receptor antagonist suppressed the PGE2- stimulated production of A beta in HEK293 cells. This stimulation was accompanied by an increase in cellular cAMP levels, and an analogue of cAMP stimulated the production of A beta, demonstrating that increases in the cellular level of cAMP are responsible for the PGE2- stimulated production of A beta. Immunoblotting experiments and direct measurement of gamma-secretase activity suggested that PGE2- stimulated production of A beta is mediated by activation of gamma-secretase but not of beta-secretase. Transgenic mice expressing the mutant type of APP showed lower levels of A beta 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 beta in vivo and in the pathogenesis of AD.