星形胶质细胞AnxA2异常增加在糖尿病海马神经元退行性变中的作用及机制研究

Astrocytes can significantly affect the neighboring neurons of diabetic hippocampus through production and release of pro-inflammatory cytokines. In the previous work, we found that Annexin A2 (AnxA2) was co-localized with the astrocytes marker protein GFAP. Increased number of AnxA2-positive astrocytes and fluorescence intensity were detected in the hippocampus of diabetic rats. And, over-expression of AnxA2 not only promoted generation of inflammation factor, but also blocked the anti-inflammatory effect of nicotine, a alpha7 nicotinic acetylcholine receptor (α7nAchR ) agonist. We speculate that AnxA2 has both direct and indirect effects on inflammatory processes, and the indirect effect operated through inhibiting the α7nAchR-mediated anti-inflammatory pathway, thus accelerates neuronal degeneration in diabetes. It was reported that AnxA2 can bind to the species sequence in 3' untranslated region (3'UTR) of mRNA, which was contained in the α7nAch 3'UTR. Also, AnxA2 regulated internalization of several receptors. In order to elucidate the mechanism of AnxA2 in regulating α7nAchR anti-inflammatory pathway, the project works in 2 key areas: α7nAchR mRNA translation and α7nAchR internalization, using immunoprecipitation experiments in α7nAchR-mutant cells. Together, the project will reveal a potential pathogenesis of diabetic neurodegeneration.

糖尿病时异常活化的星形胶质细胞释放大量炎症因子而影响海马神经元功能。我们发现：糖尿病大鼠海马区AnxA2阳性星形胶质细胞数目及阳性强度均明显增加；过表达AnxA2直接促进炎症因子生成的同时，能取消尼古丁（α7nAchR激动剂）介导的抗炎作用。我们推测：除直接促炎作用外，AnxA2还可能通过干扰α7nAchR介导的胆碱能抗炎通路间接促进星形胶质细胞生成炎症因子，而加速海马神经元退行性变。因α7nAchR3'UTR含可能与AnxA2结合的特殊序列，且AnxA2可调控多种受体的内化。本项目拟在确认AnxA2介导海马神经元退行性变的基础上，将α7nAchR3'UTR的特殊序列、α7nAchR胞内区及跨膜区各结构域分别进行突变，结合免疫共沉淀技术，从α7nAchRmRNA翻译及内化两方面探讨AnxA2干扰α7nAchR介导的胆碱能抗炎通路的机制。本项目有助于阐明糖尿病海马神经元退行性变的发病机制。

糖尿病（diabetes mellitus，DM）慢性并发症可累及中枢神经系统，导致认知障碍。糖尿病时异常活化的星形胶质细胞释放大量炎症因子而影响海马神经元功能。本项目在确认星形胶质细胞AnxA2异常增加介导海马神经元退行性变的基础上，从α7nAchRmRNA翻译及内化两方面探讨AnxA2干扰α7nAchR介导的胆碱能抗炎通路的机制。结果显示：①糖尿病大鼠海马区AnxA2阳性星形胶质细胞数目及阳性强度均明显增加；②过表达AnxA2直接促进炎症因子生成的同时，能取消尼古丁（α7nAchR激动剂）介导的抗炎作用； ③ AnxA2除直接促炎作用外，还可通过干扰α7nAchR介导的胆碱能抗炎通路间接促进星形胶质细胞生成炎症因子，而加速海马神经元退行性变。本项目为阐明糖尿病海马神经元退行性变的发病机制提供了理论基础。