Genetic Deletion of cyclooxygenase-1 ameliorates neuroinflammation and cognitive impairment in 5×FAD mice

Abstract

AbstractBackground:Neuroinflammation is one of the most important contributing factors for the pathogenesis of Alzheimer’s disease (AD). Cyclooxygenase-1 (COX-1) is distinctly expressed in microglia and involved in microglia activation and neuroinflammation in the AD. However, the molecular mechanisms by which COX-1 regulated microglia activation and participated in AD progression remains unclear. This study was designed to investigate the cellular and molecular mechanisms underlying COX-1 regulation of neuroinflammation.Methods:C57BL/6J, 5×FAD and 5×FAD/COX-1 knockout (KO) mice of different ages (e.g. 3-month-old, 6-month-old, 9-month-old) were used. Motor function and cognitive ability were evaluated using the open field test, novel-object recognition test and Morris water maze tests. The deposition of amyloid beta (Aβ) was examined by Thioflavin-S fluorescence, and neuroinflammation was investigated by immunohistochemistry, immunofluorescence and immunoblotting.Results:Konock out (KO) of COX-1 improved cognitive impairment and motor deficits, and reduced the accumulation of Aβ plaques in the cerebral cortex and hippocampus. COX-1 KO promoted microglia transition from M1 to M2 status, and reduced NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome. This was mediated by the inhibition of prostaglandin E2(PGE2)/EP2 pathway and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-nuclear factor-κB (NFκB) p65 axis.Conclusions:COX-1 may contribute to the impairment of clearance Aβ and exacerbation of neuroinflammation which led to cognitive deficits in 5×FAD transgenic mice. The effects of COX-1 were mediated through PGE2/EP2 pathway which activated cAMP-PKA-NFκB p65 axis and NLRP3 inflammasome. The results suggest that the inhibition of COX-1 may be a potential pharmacological approach for the treatment of AD.