激活大脑类淋巴-脑膜淋巴系统清除α-synuclein阳性包涵体治疗帕金森病的食蟹猴模型构建及机制研究

Meningeal lymphatic vessels were first discovered in 2015, which subverts the previous assumption of neuroimmunology that brain is an immunoprivileged organ. However, the glymphatic-meningeal lymphatic system that is not similar with peripheral immune system. Recent studies show that the glymphatic-meningeal lymphatic system is an important pathway for clearance of metabolites and abnormal macromolecules in brain during sleep, but little is known about its role in diseases. The formation and the propagation in central nervous system of α-synuclein (α-syn) inclusions are the major pathologic process of Parkinson's disease (PD). Clearance of α-syn inclusions in brain is the highlight of the therapeutic target in PD. In our previous study, α-syn fibers-induced mice model of PD was successfully constructed and α-syn was detected in meningeal lymphatic vessels and deep cervical lymph node. Further induced proliferation or deficiency of meningeal lymphatic vessels can regulate the clearance or aggregation of α-syn inclusions in brain. The results suggest that α-syn inclusions in mice brain can be cleared through glymphatic-meningeal lymphatic pathway. In this research project, we intend to establish the first cynomolgus macaque model for PD treatment by regulating glymphatic-meningeal lymphatic system to clear up α-syn inclusions. We will try to establish a better platform to study immunotherapy for PD and other α-synucleinopathies in primate.

2015年脑膜淋巴管首次被发现，它颠覆了神经免疫学的基本假设，大脑非免疫豁免器官，而存在与外周不尽相同的类淋巴-脑膜淋巴系统。研究证实睡眠状态下类淋巴-脑膜淋巴系统是脑组织代谢产物和异常大分子的重要清除途径，但其在疾病中的作用研究甚少。α-synuclein（α-syn）包涵体在中枢神经系统形成并沿轴突投射播散是帕金森病（PD）主要病理过程，清除脑组织中α-syn包涵体成为攻克PD的靶标。本项目前期研究：成功构建α-syn异构体诱导的小鼠PD模型，并在脑膜淋巴管及颈深淋巴结检测到α-syn包涵体；调控脑膜淋巴管的增生或缺失可诱导α-syn包涵体在脑组织的清除或聚集。此结果提示：脑组织内α-syn包涵体可被小鼠大脑类淋巴-脑膜淋巴系统清除。本项目拟构建国内外首个调控脑类淋巴-脑膜淋巴系统清除α-syn阳性包涵体治疗PD的非人灵长类模型，为探索PD等α-突触核蛋白病的免疫治疗提供新的方向。

2015年脑膜淋巴管首次被发现，它颠覆了神经免疫学的基本假设，大脑非免疫豁免器官，而存在与外周不尽相同的类淋巴-脑膜淋巴系统。研究证实睡眠状态下类淋巴-脑膜淋巴系统是脑组织代谢产物和异常大分子的重要清除途径，但其在疾病中的作用研究甚少。α-synuclein（α-syn）包涵体在中枢神经系统形成并沿轴突投射播散是帕金森病（PD）主要病理过程，清除脑组织中α-syn包涵体成为攻克PD的靶标。本项目前期研究：成功构建α-syn异构体诱导的小鼠PD模型，并在脑膜淋巴管及颈深淋巴结检测到α-syn包涵体；调控脑膜淋巴管的增生或缺失可诱导α-syn包涵体在脑组织的清除或聚集。此结果提示：脑组织内α-syn包涵体可被小鼠大脑类淋巴-脑膜淋巴系统清除。本项目拟构建国内外首个调控脑类淋巴-脑膜淋巴系统清除α-syn阳性包涵体治疗PD的非人灵长类模型，为探索PD等α-突触核蛋白病的免疫治疗提供新的方向。