Genetic model of selective COX2 inhibition improve learning and memory ability and brain pathological changes in 5xFAD mouse

Alzheimer's disease (AD) is the most common neurodegenerative disease that leads to dementia. Its pathogenesis is very complex, and inflammation is one of the main pathophysiological mechanisms of AD. Non-steroidal anti-inflammatory drugs (NSAIDs), which mainly target cyclooxygenase (COX) activity, are used to reduce the risk of AD, but several side effects limit their application. Here we assess the effect of Cyclooxygenase-2 (COX2) catalytic activity on learning ability and AD pathology using 5x Familial Alzheimer's Disease (FAD) mice with COX2 inhibition (5xFAD/COX2 KO), 5xFAD mice with cyclooxygenase inactivation of COX2 (5xFAD/COX2 Y385F), and 5xFAD mice with peroxidase (POX) inactivation of COX2 (5xFAD/COX2) H374Y), respectively. Our results indicate that learning ability of COX2 KO and mutants is improved compared to 5xFAD mice, further investigations show that Aβ depositions are reduced, microglia and astrocytes homeostasis are changed in COX2 KO and mutants. Especially, there is more responsive microglia in the brain of 5xFAD/COX2 Y385F mice, and Aβ depositions are more effectively cleaned at old age. Taken together, these results identify a role of COX2 Y385F in regulating microglia function and may have important implications for future treatment of AD.