基于调控星形胶质细胞介导的谷氨酸-谷氨酰胺循环改善海马niche探讨楮实子促神经发生治疗AD的作用及机制

成年海马神经发生异常被认为与AD发生发展密切相关，由此导致特定脑区神经元溃变丢失是AD无法治愈的原因，故促神经发生将成为治疗AD的有效策略。神经发生高度依赖海马微环境(niche)的状态，星形胶质细胞(AS)与niche内所有细胞均有接触，通过谷氨酸-谷氨酰胺循环(GGC)调控神经营养因子和神经毒素释放改善海马niche状态，是促神经发生的关键因素。楮实子具补肾益髓之功效，前期研究发现楮实子水提物可提高AD小鼠脑内新生神经元数量、改善其认知功能，增加其脑组织中NAA和Gln含量，但作用机制尚不明确。本项目拟对楮实子不同提取部位进行化学组分分析；利用AD斑马鱼对其促神经发生的有效部位进行筛选；利用APP-NSCs/AS共培养模型及AD小鼠对其有效部位促神经发生的药效进行验证，并深入解析其分子机制，为充分开发楮实子药用价值提供理论依据，为中药再生修复治疗AD等神经退行性病变提供新思路和新方法。

The abnormality of adult hippocampal neurogenesis is considered to be closely related to the occurrence and development of AD, the resulting progressive neuronal loss in specific brain areas is the reason why AD cannot be cured. Therefore, promoting neurogenesis will become an effective strategy for the treatment of AD. Neurogenesis is highly dependent on the state of the hippocampal microenvironment (niche). Astrocytes (AS) are an important member and contacted with all cell types in the niche. Through the glutamate-glutamine cycle (GGC), AS can regulate the balance of neurotrophic factors and neurotoxins, so that to improve the niche state, which is a key factor in promoting neurogenesis. Fructus broussonetiae has the effect of tonifying kidney and marrow. Our previous studies have found that the Fructus broussonetiae extract can increase the number of new born neurons, improve the cognitive function and increase the content of NAA and Gln in the brain of AD mice. However, its mechanism is still unclear. Based on the previous work, this project intends to analyze the chemical components of different extracted parts of Fructus Broussonetiae, screening its effective parts using AD zebrafish model, verifying and analyzing its efficacy and molecular mechanism using APP-NSCs/AS co-culture model and AD mice. The above research provides a theoretical basis for fully exploiting the medicinal value of Fructus Broussonetiae, and also provides new ideas and methods for the regeneration and repair of traditional Chinese medicine in treating neurodegenerative diseases such as AD.