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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Reactive microglia enhance the transmission of exosomal α-synuclein via toll-like receptor 2
Yun Xia1, Guoxin Zhang2, Liang Kou1
1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Abstract:
Increasing evidence suggests that microglial activation is strongly linked to the initiation and progression of Parkinson's disease. Cell-to-cell propagation of α-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 α-synuclein pathology. Recent data revealed that plasma exosomes derived from Parkinson's disease patients (PD-EXO) carry pathological α-synuclein and target microglia preferentially. Hence, PD-EXO are likely a key tool for investigating the role of microglia in α-synuclein transmission. We showed that intrastriatal injection of PD-EXO resulted in the propagation of exosomal α-synuclein from microglia to neurons following microglia activation. Toll-like receptor 2 (TLR2) in microglia was activated by exosomal α-synuclein and acted as a crucial mediator of PD-EXO-induced microglial activation. Additionally, partial microglia depletion resulted in a significant decrease of exogenous α-synuclein in the substantia nigra. Furthermore, exosomal α-synuclein internalization was initiated by binding to TLR2 of microglia. Excessive α-synuclein phagocytosis may induce the inflammatory responses of microglia and provide the seed for microglia-to-neuron transmission. Consistently, TLR2 silencing in microglia mitigated α-synuclein pathology in vivo. Overall, the present data support the idea that the interaction of exosomal α-synuclein and microglial TLR2 contribute to excessive α-synuclein phagocytosis and microglial activation, which lead to the further propagation and spread of α-synuclein pathology, thereby highlighting the pivotal roles of reactive microglia in α-synuclein transmission.
Insights
Microglia activation and alpha-synuclein spread are key in Parkinson's disease. Patient exosomes carrying alpha-synuclein activate microglia via TLR2, driving disease pathology and transmission.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial activation is implicated in Parkinson's disease (PD) pathogenesis.
- Alpha-synuclein pathology spread is a hallmark of PD, traditionally focused on neuronal transmission.
- Microglia, the brain's immune cells, are increasingly recognized for their role in PD progression.
Purpose of the Study:
- To investigate the role of microglia in the cell-to-cell transmission of alpha-synuclein pathology.
- To explore the mechanism by which Parkinson's disease patient-derived exosomes (PD-EXO) influence microglial activation and pathology spread.
- To determine the involvement of Toll-like receptor 2 (TLR2) in mediating PD-EXO effects on microglia.
Main Methods:
- Intrastriatal injection of PD-EXO in a mouse model.
- Analysis of alpha-synuclein propagation from microglia to neurons.
- Assessment of microglial activation markers and inflammatory responses.
- Investigation of TLR2 activation and signaling pathways.
- Microglia depletion and TLR2 silencing experiments.
Main Results:
- PD-EXO carrying pathological alpha-synuclein preferentially target and activate microglia.
- Microglial activation by PD-EXO leads to the propagation of alpha-synuclein from microglia to neurons.
- Exosomal alpha-synuclein binding to microglial TLR2 is crucial for PD-EXO-induced activation.
- Microglia depletion significantly reduced exogenous alpha-synuclein in the substantia nigra.
- TLR2 silencing in microglia attenuated alpha-synuclein pathology in vivo.
Conclusions:
- The interaction between exosomal alpha-synuclein and microglial TLR2 drives excessive phagocytosis and microglial activation.
- This process contributes significantly to the propagation and spread of alpha-synuclein pathology in Parkinson's disease.
- Reactive microglia play a pivotal role in mediating alpha-synuclein transmission, highlighting TLR2 as a potential therapeutic target.
