Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neu‐ronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro. The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR‐124‐3p increased most apparently in the miRNAs. We found that miR‐124‐3p promoted the anti‐inflamed M2 polarization in microglia, and microglial exosomal miR‐124‐3p inhibited neuronal inflammation in scratch‐injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR‐124‐3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR‐124‐3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR‐124‐3p by pathway analysis. We proved that it was directly targeted by miR‐124‐3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR‐124‐3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR‐124‐3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreasedexpressiononRhoAand neurodegenerative proteins [Aß‐peptide and p‐Tau]. It also improved the neurologic outcome and inhibited neuro‐inflammation in mice with rTBI. Taken together, increased miR‐124‐3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR‐124‐3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR‐124‐3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.—Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR‐124‐3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J. 32, 512‐528 (2018). www.fasebj.org

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.

Amyloid-β (Aβ) is the predominant pathologic protein in Alzheimer’s disease (AD). The production and deposition of Aβ are important factors affecting AD progression and prognosis. The deposition of neurotoxic Aβ contributes to damage of the blood–brain barrier. However, the BBB is also crucial in maintaining the normal metabolism of Aβ, and dysfunction of the BBB aggravates Aβ deposition. This review characterizes Aβ deposition and BBB damage in AD, summarizes their interactions, and details their respective mechanisms.

Alzheimer’s disease (AD) has been a devastating public health with the development of global aging. Approaches for reducing the current AD epidemic are becoming a primary focus of human healthcare due to the lack of achieved lasting and complete remission strategies to treat AD with the characteristics of heterogeneity and complexity. Exosomes, which is the new emerging approach to intercellular communication, provide novel perspective on identified therapeutic strategies of AD. Mesenchymal stem cell-derived exosomes (MSC-exos) are emerging to be an appealing therapeutic tool for AD, with the donor-derived properties and the characteristics of minimal immunogenicity, effortless storage, nature delivery vehicles, and low risks of tumor formation based on the previous researches. In this review, we elaborate the mechanism of MSC-exos in the treatment of AD and discuss limitations in the clinical application.