Cyclooxygenase-2 promotes amyloid plaque deposition in a mouse model of Alzheimer's disease neuropathology

Several epidemiologic studies have reported that cyclooxygenase (COX) inhibitors prevent/delay the onset of Alzheimer's disease (AD). Recent experimental studies suggest that these compounds can also diminish amyloid-β (Aβ) neuropathology in rodent models of AD. To explore the relationship of COX expression to Aβ neuropathology, we crossed mice expressing both mutant amyloid precursor protein [K670N/M671L (APP_swe)] and mutant PS1 (A246E) with mice expressing human COX-2 selectively in neurons. We show here that human COX-2 expression in APP_swePS1/COX-2 mice induces potentiation of brain parenchymal amyloid plaque formation and a greater than twofold increase in prostaglandin E₂ production, at 24 months of age. This increased amyloid plaque formation coincided with a preferential elevation of Aβ_1-40 and Aβ_1-42 with no change in total amyloid precursor protein (APP) expression/content in the brain. Collectively these data suggest that COX-2 influences APP processing and promotes amyloidosis in the brain.