前期工作显示芸薹生链格孢发酵的次生代谢产物具有神经保护作用，并分离得到5/8/5环与5/9/5（5/8/5）环系以C12-C18’相连的壳梭菌素新颖二聚体，药理实验证明其对诱导损伤的PC12及BV-2神经细胞具有保护作用，并能显著改善AD小鼠学习记忆功能障碍。故本项目锁定链格孢壳梭菌素类型化学体系，采用OSMAC策略，放大发酵并定向富集和分析成分，运用现代色谱学的分离手段和波谱学鉴定技术，快速精准分离和鉴定化合物结构。并应用神经系统疾病药物筛选的理想模型-秀丽线虫，构建PolyQ介导的HA759线虫的ASH神经元损伤模型，从线虫内源性PolyQ 聚集抑制作用、体外趋化行为学和延长寿命三个方面评价化合物对神经元衰退的缓解作用，得到针对调控DAF-16/FOXO 通路上机制明确的新颖先导化合物，丰富链格孢的神经保护药效物质基础，也为天然产物在神经退行性疾病药物领域的开发利利用提供新型研发模型。

Previous work showed that novel dimers of fusicoccane isolated from Alternaria brassicae bearing an unprecedented 5/8/5 - 5/9/5 or 5/8/5 - 5/8/5fused carbocyclic skeleton rings connected by C12-C18', and secondary metabolites demonstrated different protective effects against neurocytotoxicity in cultured PC12 and BV-2 cells and could significantly improve learning and memory dysfunction in AD mice. Therefore, this project will aim to the enlarge fermentation by OSMAC strategy, enrichment and analysis by HPLC-MS-MS, isolation using modern chromatographic separation methods and identification by spectroscopic techniques. Their activities will be evaluated by nematode endogenous polyQ aggregation inhibitory effects, the change in behavior trend and lifespan assay in Caenorhabditis elegans. Furthermore, the components’ neuroprotective mechanism will be elucidated by DAF-16 nuclear localization and oxidative stress assay in C. elegans. This subject will further clarify the neuroprotective components for the development in the field of neurological diseases of natural products resources.