骨髓基质神经干细胞联合法舒地尔多视角治疗AD的探索

Nowadays, the treatment of AD remains difficult. We establish new ways to explore combination therapy of Rho kinase inhibitor Fasudil and bone marrow stromal cells (MSCs) for AD by virtue of Fasudil that display anti-inflammation,synapse formation and mobilization of neural stem cells(NSCs): 1) To avoid pathogenic mechanism that is still not clear, we directly focus on basic pathological features of AD including inflammatory response, synaptic damage and neuronal degeneration. We design a combination therapy of AD model, that is, MSCs combine with Fasudil. At the same time, we will compare intravenous or nasal routes of MSCs administration, achieving a maximum overly and complementary effect of MSCs and Fasudil. 2) By combination therapy of different routes, we try to explore peripheral immunomodulation and inflammation responses, including regulation of T cell subsets, polarization of macrophage subsets, formation of immunogenicity and relationship between peripheral immune/inflammatory responses and AD pathology. 3) By combination therapy of different routes, we try to explore the improvement of central nervous system microenvironment, including brain localization of transplanted cells, interaction with host cells (microglia and astrocytes) in the brain, inflammatory microenvironment, synaptic formation and mobilization of endogenous NSCs. We attempt to pay close attention to multi-targets for the neuroprotection and neuroregeneration of AD, providing possible therapeutic strategies in future treatment of AD.

目前阿尔茨海默病（AD）的治疗仍令人失望，本课题应用Rho激酶抑制剂Fasudil的抗炎、促神经突触再生和动员神经干细胞的特征，探寻Fasudil和骨髓基质干细胞（MSCs）联合治疗AD的新途径：1）拟避开仍不清晰的致病机制，针对AD患者炎性反应、突触损害和神经变性的病理特征，利用Fasudil的上述特征，联合自体MSCs设计治疗实验性AD的方案。经静脉或鼻途径，最大限度达到MSCs和Fasudil作用叠加和功能互补；2）研究不同途径联合治疗对外周免疫炎症的调节，包括T细胞亚群调节、巨噬细胞极化、免疫原性形成以及外周免疫炎症反应与AD病理变化之间的关联；3）研究不同途径联合治疗对中枢细胞反应的影响，包括移植细胞脑内定位、与脑内宿主细胞的相互作用、对神经突触形成和内源性神经干细胞的影响。拟构建中枢立体多元的作用靶点，形成神经元保护和再生所必要的微环境，为联合治疗AD奠定理论和实验依据。

本课题在前期的研究基础上，首次将Rho激酶抑制剂Fasudil用于治疗AD动物模型，根据研究证实Fasudil具有抗炎、免疫调节、促进神经突触再生以及动员神经干细胞等新的多元作用，进一步探究了将Fasudil结合骨髓基质干细胞（BMSCs）联合治疗对AD动物模型临床认知功能、外周免疫炎症调节和中枢神经系统的影响，为临床应用Rho激酶抑制剂或联合治疗AD提供实验室依据。经过三年的研究，取得如下实验依据和研究结果：1）应用国际通用APP/PSN（B6）双转基因动物模型模拟AD发病，通过动物行为学检测，建立AD动物模型空间认知功能指标，为开展本课题研究提供可靠的疾病模型和临床认知功能观察标准；2）围绕生物学标志物测定，建立一系列AD疾病模型生物学检测指标，为后期开展Rho激酶抑制剂及联合BMSCs治疗AD疾病模型效果评价提供生物学标准；3）应用Rho激酶抑制剂Fasudil治疗AD动物模型APP/PSN（B6）双转基因鼠观察临床行为学改变和测定标志性生物化学指标，进一步探讨Fasudil治疗AD动物模型中枢和外周炎症因子/炎症信号通路；4）应用Fasudil联合BMSCs干预AD动物模型，探究外周免疫炎症的协同调节作用，为围绕Rho/Rho激酶信号通路，构建外周-中枢立体多元的神经保护和神经再生联合治疗AD奠定理论基础和实验依据，探索防治AD的新途径。