Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
复制标题
DOI：
10.1093/brain/awab122
复制
发表时间：
2021-04-01
期刊：
影响因子：
14.5
通讯作者：
Wang, Tao
中科院分区：
文献类型：
--
作者：
Xia, Yun;Zhang, Guoxin;Wang, Tao
越来越多的证据表明，小胶质细胞的激活与帕金森病的发生和发展密切相关。突触核蛋白病理的细胞间传播是帕金森病的一个突出特征，这类研究的重点主要集中在神经元上。然而，最近的研究以及本文中包含的数据表明，小胶质细胞是大脑中的主要吞噬细胞，在α -突触核蛋白病理的传播中起直接作用。最近的数据显示，来自帕金森病患者的血浆外泌体（PD-EXO）携带病理性α -突触核蛋白，并优先靶向小胶质细胞。因此，PD-EXO可能是研究小胶质细胞在α -突触核蛋白传递中的作用的关键工具。我们发现，在小胶质细胞激活后，纹状体内注射PD-EXO导致外泌体α -突触核蛋白从小胶质细胞向神经元增殖。外泌体α -突触核蛋白激活小胶质细胞中的toll样受体2 (TLR2)，并作为pd - exo诱导的小胶质细胞激活的重要介质。此外，部分小胶质细胞缺失导致黑质外源性α -突触核蛋白显著减少。此外，外泌体α -突触核蛋白内化通过与小胶质细胞的TLR2结合而启动。过量的α -突触核蛋白吞噬可诱导小胶质细胞的炎症反应，并为小胶质细胞-神经元传递提供种子。一致地，小胶质细胞中TLR2的沉默减轻了α -突触核蛋白的体内病理。总的来说，目前的数据支持外泌体α -突触核蛋白和小胶质TLR2的相互作用导致α -突触核蛋白过度吞噬和小胶质细胞活化，从而导致α -突触核蛋白病理的进一步传播和扩散，从而突出了反应性小胶质细胞在α -突触核蛋白传递中的关键作用。
Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson's disease. Cell-to-cell propagation of alpha-synuclein pathology is a highlighted feature of Parkinson's disease, and the focus of such research has been primarily on neurons. However, recent studies as well as the data contained herein suggest that microglia, the primary phagocytes in the brain, play a direct role in the spread of alpha-synuclein pathology. Recent data revealed that plasma exosomes derived from Parkinson's disease patients (PD-EXO) carry pathological alpha-synuclein and target microglia preferentially. Hence, PD-EXO are likely a key tool for investigating the role of microglia in alpha-synuclein transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal alpha-synuclein from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal alpha-synuclein and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous alpha-synuclein in the substantia nigra. Furthermore, exosomal alpha-synuclein internalization was initiated by binding to TLR2 of microglia. Excessive , alpha-synuclein phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-toneuron transmission. Consistently, TLR2 silencing in microglia mitigated alpha-synuclein pathology in vivo. Overall, the present data support the idea that the interaction of exosomal alpha-synuclein and microglial TLR2 contribute to excessive , alpha-synuclein phagocytosis and microglial activation, which lead to the further propagation and spread of alpha-synuclein pathology, thereby highlighting the pivotal roles of reactive microglia in alpha-synuclein transmission.