J. Neurochem. (2012) 120, 795–805.
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 E2 (PGE2) stimulates the production of Aβ through both EP2 and EP4 receptors and that activation of the EP4 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 EP2 or EP4 receptors, respectively. Mice lacking the EP4 receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP4 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 EP4 receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP4 receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.