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

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 b-amyloid abnormalities and impaired cognitive function. Microglial exosomes have been reported to be involved in the transportation, distribution, and clearance of b-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 b-amyloid proteolytic breakdown, thereby inhibiting b-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.

Extracellular Vesicle Proteins and MicroRNAs as Biomarkers for Traumatic Brain Injury

“…In a 2020 study of rTBI, miR-124-3p levels in MDE were found to be significantly altered in the acute, sub-acute, and chronic phases following the injury (180). Intravenous administration of MDE with upregulated miR-124-3p alleviated neurodegeneration in repetitive scratch-injured neurons, the effects of which were exerted by miR-124-3p targeting RelA, an inhibitory transcription factor of apolipoprotein E (ApoE) that promotes β-amyloid proteolytic breakdown, thereby inhibiting β-amyloid abnormalities (180).…”

Exosomal miRNAs in tumor microenvironment

“…In metabolism and cardiovascular diseases, exosomes induce metabolic disorders in adipocytes and islet cells [66,67]. Exosomes may impair the formation of neurotoxic oligomers and promote neurodegeneration [68][69][70]. More importantly, exosomes are associated with tumor growth, angiogenesis, metastasis, sensitivity to chemotherapy, and immune evasion [47,71,72].…”

Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer’s Disease Model by Binding to Itpkb

“…EV-mediated delivery of miRNAs is reported to attenuate neurodegeneration and restore cognitive function in a repetitive mild traumatic brain injury (rmTBI) model that simulates aspects of AD (Ge et al, 2020). It is noted that miR-711 has been identified to modulate anti-inflammatory pathways and M2-like activation phenotype, as was demonstrated previously in the context of neuroinflammatory reactions revealed by microarray expression profiling (Freilich et al, 2013).…”