The Roles Of Toll-like Receptor 2 In Chronic Intermittent Hypoxia-induced Neurocognitive Impairment And Its Molecular Mechanism

Objective:Obstructive sleep apnoea syndrome(OSAS)is a highly prevalent respiratory disorder characterized by repeated upper airway obstruction or repetitive central apneic episodes.The main pathophysiologic feature of OSAS is chronic intermittent hypoxia(CIH)and sleep fragmentation.A number of evidence suggested that CIH led to various cognitive impairments.CIH-mediated neurocognitive dysfunctions were mainly relative to oxidative stress and neruoinflammation in hippocampus.Toll-like receptors have been suggested playing a role in neuroinflammation of CNS and the most members of TLRs were widely expressed in the microglia,astrocytes and neuron,especially toll-like receptor 2(TLR2).In addition,TLR2 could activate the microglial cells,increase the release of pro-inflammatory mediators,and promote the production of ROS,which finally lead to neuronal impairments.However,the function of TLR2 played in CIH-induced neurocognitive impairment was still unclear and the potential molecular mechanisms remain to be explored.In order to better understand the mechanisms of CIH-induced cognitive disorders,we studied the effect of TLR2 on hippocampal damages after CIH treatment.Methods:The cognitive factions of C57 BL/6 mice were detected via 3-chambered social test and Morris water maze after CIH treatment.The CIH induced morphologic damage of cells in hippocampus was evaluated by HE staining.The expression of NeuN,Iba-1 and GFAP were investigated through immunofluorescence.That represented the changes of neuron,microgila and astrocyte after CIH exposure.Elisa was used to show the production of inflammatory factors,including TNF-?,IL-6,IL-1?.In addition,the expression levels of TLR2,MyD88,TRAF6 and NF-?B were detected by western blot to explore the related mechanisms of TLR2 in CIH-mediated cognitive deficits.Results:Chronic intermittent hypoxia resulted in neurocognitive deficits in C57 BL/6 mice,especially the social memory,spatial learning and memory.In addition,the data of HE and immunofluorescence showed that the hippocampal impairments,the activation of microglia and the proliferation of astrocyte were attenuated in TLR2 KO + CIH group compared with WT+CIH group.According to the results of Western blot and ELISA,these results indicated that inhibiting TLR2 could decrease the expression of related proteins and the generation of inflammatory cytokines.Conclusion:Our results indicated that CIH induced the neural cell damage in hippocampus and it made further abnormal effects of neurocognitive behaviors in mice,including the social recognition,spatial learning and memory.Notably,the cognitive dysfunction was attenuated via inhibiting the TLR2-MyD88-NF-?B signaling pathway in this study.