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Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI
Xintong Ge1, Mengtian Guo2, Tianpeng Hu2
1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin Neurological Institute, Tianjin 300052, China; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Tianjin Neurological Institute, Tianjin 300052, China.
Abstract:
Repetitive mild traumatic brain injury (rmTBI) is considered to be an important risk factor for long-term neurodegenerative disorders such as Alzheimer's disease, which is characterized by β-amyloid abnormalities and impaired cognitive function. Microglial exosomes have been reported to be involved in the transportation, distribution, and clearance of β-amyloid in Alzheimer's disease. However, their impacts on the development of neurodegeneration after rmTBI are not yet known. The role of miRNAs in microglial exosomes on regulating post-traumatic neurodegeneration was investigated in the present study. We demonstrated that miR-124-3p level in microglial exosomes from injured brain was significantly altered in the acute, sub-acute, and chronic phases after rmTBI. In in vitro experiments, microglial exosomes with upregulated miR-124-3p (EXO-124) alleviated neurodegeneration in repetitive scratch-injured neurons. The effects were exerted by miR-124-3p targeting Rela, an inhibitory transcription factor of ApoE that promotes the β-amyloid proteolytic breakdown, thereby inhibiting β-amyloid abnormalities. In mice with rmTBI, the intravenously injected microglial exosomes were taken up by neurons in injured brain. Besides, miR-124-3p in the exosomes was transferred into hippocampal neurons and alleviated neurodegeneration by targeting the Rela/ApoE signaling pathway. Consequently, EXO-124 treatments improved the cognitive outcome after rmTBI, suggesting a promising therapeutic strategy for future clinical translation.
Insights
Repetitive mild traumatic brain injury (rmTBI) can lead to neurodegeneration. Microglial exosomes carrying miR-124-3p show potential in alleviating rmTBI-induced neurodegeneration and improving cognitive function.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Repetitive mild traumatic brain injury (rmTBI) is a risk factor for neurodegenerative diseases like Alzheimer's.
- Microglial exosomes play a role in beta-amyloid metabolism in Alzheimer's disease.
- The impact of microglial exosomes on neurodegeneration following rmTBI remains unclear.
Purpose of the Study:
- To investigate the role of microRNAs (miRNAs) within microglial exosomes in regulating neurodegeneration after rmTBI.
- To explore the therapeutic potential of miR-124-3p-enriched microglial exosomes (EXO-124) in rmTBI models.
Main Methods:
- Analysis of miR-124-3p levels in microglial exosomes post-rmTBI.
- In vitro studies using cultured neurons exposed to rmTBI and treated with EXO-124.
- In vivo studies involving rmTBI mice treated with intravenously injected microglial exosomes.
- Investigation of the Rela/ApoE signaling pathway.
Main Results:
- miR-124-3p levels in microglial exosomes were altered across different phases post-rmTBI.
- EXO-124 treatment alleviated neurodegeneration in vitro by targeting Rela and promoting beta-amyloid breakdown.
- In vivo, transferred miR-124-3p from exosomes into hippocampal neurons reduced neurodegeneration via the Rela/ApoE pathway.
- EXO-124 treatment improved cognitive function in rmTBI mice.
Conclusions:
- Microglial exosomal miR-124-3p is a key regulator of neurodegeneration following rmTBI.
- Targeting the Rela/ApoE pathway with miR-124-3p offers a potential therapeutic strategy for rmTBI.
- Microglial exosome-based therapy presents a promising avenue for clinical translation in treating rmTBI-induced cognitive deficits.
