Depletion Of Senp1-Mediated Ppar Gamma Sumoylation Exaggerates Intermittent Hypoxia-Induced Cognitive Decline By Aggravating Microglia-Mediated Neuroinflammation

Intermittent hypoxia (IH)-associated cognition decline is related to the neuroinflammation of microglia. SUMOylation is a post-translational modification related to multiple human diseases, which can be reversed by SENP1. Studies showed that SENP1 and PPAR gamma play essential roles in restricting inflammation by blocking NF-kappa B activation. However, the mechanism remains unclear. Herein, we investigated the precise mechanism underlying SENP1 and PPAR gamma in cognitive decline after IH insult. Biochemical analysis results revealed that IH triggered the inflammatory response and neuronal apoptosis, increased the SUMOylation of PPAR gamma, and decreased the level of PPAR gamma compared to that in the normoxia group. After SENP1 downregulation, the inflammatory response, neuronal apoptosis and the SUMOylation of PPAR gamma were enhanced, and the level of PPAR gamma was further decreased in vitro and in vivo. However, the application of PPAR gamma agonist, GW1929, abolished the enhancement of inflammation and neuronal apoptosis in vitro. The Morris Water Maze results showed that both IH groups mice exhibited longer latency and shorter dwell-time in the goal quadrant than normoxia groups. Notably, SENP1 downregulation aggravated these alterations. Overall, these results showed that SENP1 played an essential role in IH-associated cognitive dysfunction. SENP1 depletion aggravated neuroinflammation and neuronal apoptosis via promoting the SUMOylation of PPAR gamma, reducing the level of PPAR., thus exaggerating IH-induced cognitive decline.