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

Author:

Wang Jie1,Ni Hong1,Wei luyao1,Ding Hanqing1,Guo Zhongzhao1,Yu Ying2,Luo Jia3,Ke Zun-Ji1

Affiliation:

1. The Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine

2. Department of Pharmacology and Tianjin Key Laboratory of Inflammatory Biology, Tianjin Medical University

3. Department of Pathology, University of Iowa Carver College of Medicine

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.

Publisher

Research Square Platform LLC

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