miR-181c靶向调控小胶质细胞TLR4-NF-kB信号通路参与血管性轻度认知功能损害发生发展

Vascular mild cognitive impairment (V-MCI), a pre-condition of vascular dementia, have attracted more attention. We have previously confirmed that chronic ischemia or hypoxia led to microglial activation and overproduction of neuroinflammation factors at CA1 subregion, which contributed to VMCI. We also found that microglial miR-181c could directly target TNF expression. Recently, we identified that miR-181c may potentially target Toll-like receptor 4(TLR4), which lead to activation of NF-kB signaling and neuronal apoptosis. Therefore, in this study we tried to confirm that ischemia-induced miR-181c downregulation may lead to TLR4 overexpression. TLR4 then activates NF-kB signaling and downstream neuroinflammation factors, such as TNF、IL1B、IL6 and finally induces neuronal apoptosis. In addition, overpressing miR-181c in the CA1 region could improve cognition of V-MCI rat model and prevent from cognitive impairment . Therefore, based on this study we may identify a new mechanism for miR-181c in regulating the TLR4 pathway in hypoxic microglial activation, which could provide a potential therapeutic target for V-MCI.

血管性轻度认知功能损害(V-MCI)作为血管性痴呆可能的前期状态，近年备受关注。课题组前期在国家自然科学基金青年项目中证实，慢性缺血/缺氧后海马CA1区小胶质细胞活化、炎性因子释放与V-MCI有关，并且发现miR-181c可直接调控小胶质细胞炎性因子TNF表达。后续我们在此基础上，发现miR-181c有可能通过调控TLR4表达及其下游NF-kB信号通路，参与神经炎性损伤和V-MCI。因此本研究拟证明在慢性缺血/缺氧后小胶质细胞miR-181c表达下调是否可诱导TLR4表达上调，激活NF-kB信号通路促进炎性因子（如TNF、IL1B、IL6等）表达增加，通过炎性反应损伤神经元；而当V-MCI大鼠海马CA1区恢复miR-181c表达后是否可使其认知功能得到改善。如果该假设被证实，将对于阐明V-MCI 发生发展的分子调控机制具有重要的科学价值，并为后续寻找V-MCI 新的分子干预靶点提供依据。

小胶质细胞活化和炎性细胞因子释放参与缺血/缺氧后神经炎性损伤，而microRNA调控大脑发育、介导了认知相关性疾病的发生与发展。因此本研究系统评估了血管性认知障碍发生发展过程中，小胶质细胞活化和炎性细胞因子释放是否收受到miRNA的调控。我们发现，体外OGD诱导小胶质细胞活化和炎性细胞因子释放，体内BCCAO和4-VO均可诱导海马CA1区小胶质细胞活化和炎性细胞因子过表达/分泌。我们构建了小胶质细胞活化过程中miRNA与炎性细胞因子调控网络，发现许多炎性细胞因子都受到miRNA调控。同时我们证实，缺血/缺氧诱导小胶质细胞miR-181c表达下调，miR-181c可直接调控下游靶基因TLR4及其下游NF-kB及炎性因子通路来调控神经元损伤。大鼠海马CA1区过表达miR-181c可抑制缺血后小胶质细胞活化、炎性细胞因子释放和神经元损伤，进而改善缺血后大鼠认知功能。因此，miRNA参与调控缺血/缺氧后小胶质细胞活化和炎性细胞因子释放。miR-181c通过调控炎性因子通路降低神经损伤，改善认知功能，未来有可能成为血管性认知障碍潜在干预靶点。