Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI

• Published in: Molecular therapy 2020-02, Vol.28 (2), p.503-522
• Main Authors: Ge, Xintong, Guo, Mengtian, Hu, Tianpeng, Li, Wenzhu, Huang, Shan, Yin, Zhenyu, Li, Ying, Chen, Fanglian, Zhu, Luoyun, Kang, Chunsheng, Jiang, Rongcai, Lei, Ping, Zhang, Jianning
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - metabolism; Brain Concussion - etiology; Brain Concussion - metabolism; Brain Concussion - pathology; Brain Concussion - rehabilitation; Cognition; Computational Biology - methods; Disease Models, Animal; exosomes; Exosomes - metabolism; Gene Expression Profiling; Male; Mice; microglia; Microglia - metabolism; MicroRNAs - genetics; miR-124-3p; Models, Biological; neurodegeneration; Neurodegenerative Diseases - etiology; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - rehabilitation; Neurons - metabolism; Original; repetitive mild traumatic brain injury; RNA Interference; Severity of Illness Index; Signal Transduction; Transcription Factor RelA - metabolism
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.11.017

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. [Display omitted] Ge et al. identify the upregulated miR-124-3p in microglial exosomes after repetitive mild traumatic brain injury (rmTBI) contributes to alleviating neurodegeneration via transferring into neurons and targeting Rela/ApoE signaling pathway. Microglial exosomes with upregulated miR-124-3p are a promising therapeutic tool for rmTBI with clinical application prospects.