LPS致老龄大鼠星形胶质细胞（NF）-κB信号通路激活、拮抗对海马神经元认知凋亡的影响

Postoperative cognitive dysfunction (POCD) is a popular complication in elderly patients, which severely impacts the patients' return to family and society. Various factors in perioperative period will trigger the endotoxemia and systemic inflammatory response, which plays a key role in the processing of POCD,. Astrocytes (AS) are closely related to central inflammation and synaptic plasticity in hippocampus neuron (HN). It has rarely been reported whether LPS-induced changes in synaptic plasticity is directly associated with NF-κB pathway activation in AS and whether or not the antagonizing of the pathway can reverse it. Our preliminary results demonstrated that intraperitoneal injection of LPS can activate NF-κB pathway in AS, followed by neuronal apoptosis and the releasing of central inflammatory cytokines. The research will focus on: 1.The time course characteristics of the activation of NF-κB pathway and inflammatory status in AS and HN by intraperitoneal injection of LPS in aged rats, the effects on HN synapses plasticity and cognitive function, and the reversing HN changes' possibility by antagonizing NF-κB pathway in AS. 2. In vitro, analyzing the effect of in-vivo activated AS of NF-κB pathway or adding inhibitor on co-culturing-HN apoptosis and synapses plasticity. We want to elucidate: 1.The role of AS in the LPS-induced HN inflammation and cognitive apoptosis in aged rats. 2. Exploring the time window of atagonizing the activation of NF-κB pathway in AS and its reversing consequence.

老年患者术后认知功能障碍(POCD)发病率高，严重影响患者回归家庭与社会能力。围术期各种因素导致内毒素血症和全身炎性反应，对POCD发生发展具有重要作用。星形胶质细胞（AS）与中枢炎症和海马神经元（HN）突触可塑性关系密切。LPS致HN突触可塑性改变是否与AS的NF-κB通路激活直接相关，拮抗该通路能否逆转未见报道。前期研究结果表明，腹腔内注射LPS可激活大鼠海马ASNF-κB通路，促进神经元凋亡和中枢炎性因子生成。研究内容：1.老龄大鼠腹腔注射LPS激活AS NF-κB通路与HN炎性状态的时程特征，以及对HN突触可塑性和认知功能的影响；拮抗AS NF-κB通路的逆转效应。2.激活NF-κB通路或者加入该通路抑制剂的AS细胞，体外与HN共培养，研究对HN凋亡和突触可塑性的影响。阐明：1.AS在LPS致老龄大鼠HN炎性状态以及认知凋亡中的作用；2.探索拮抗AS NF-κB通路的时间窗和逆转。

神经炎症反应是认知功能障碍机制之一。小胶质细胞是神经炎症的重要来源，而星形胶质细胞在神经炎症的角色尚未阐明。NF-κB信号通路是神经炎症反应重要信号通路。神经炎症可能改变突触可塑性导致认知功能障碍。本研究探讨单次腹腔注射后老龄鼠星形胶质细胞NF-κB信号通路激活对海马神经元突触后蛋白和认知功能的影响。研究结果表明全身炎症反应短且早于神经炎症反应。LPS诱导海马区NF-κB p65和星形胶质细胞源性IL-1β持续表达。海马区星形胶质细胞源性炎症因子表达上调,同时神经元突触后蛋白下调。LPS激活体外培养星形胶质细胞源性NF-κB p65通路激活和炎症因子表达。这些结果揭示星形胶质细胞是延迟性神经炎症反应重要来源。星形胶质细胞NF-κB信号通路在其中扮演重要角色。