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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 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.

SUBMITTER: Ge X

PROVIDER: S-EPMC7001001 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Ge Xintong X Guo Mengtian M Hu Tianpeng T Li Wenzhu W Huang Shan S Yin Zhenyu Z Li Ying Y Chen Fanglian F Zhu Luoyun L Kang Chunsheng C Jiang Rongcai R Lei Ping P Zhang Jianning J

Molecular therapy : the journal of the American Society of Gene Therapy 20191127 2

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 ...[more]

PMID: 31843449

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Project description:Cognitive impairment induced by postoperative pain severely deteriorates the rehabilitation outcomes in elderly patients. The present study focused on the relationship between microglial exosome miR-124-3p in hippocampus and cognitive impairment induced by postoperative pain. Cognitive impairment model induced by postoperative pain was constructed by intramedullary nail fixation after tibial fracture. Morphine intraperitoneally was carried out for postoperative analgesia. Morris water maze tests were carried out to evaluate the cognitive impairment, while mRNA levels of neurotrophic factors (BDNF, NG) and neurodegenerative biomarker (VILIP-1) in hippocampus were tested by q-PCR. Transmission electron microscope was used to observe the axon degeneration in hippocampus. The levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6), the levels of anti-inflammatory factors (Ym, Arg-1, IL-10) and microglia proliferation marker cyclin D1 in hippocampus were measured to evaluate microglia polarization. Bioinformatics analysis was conducted to identify key exosomes while BV-2 microglia overexpressing exosome miR-124-3p was constructed to observe microglia polarization in vitro experiments. Exogenous miR-124-3p-loaded exosomes were injected into hippocampus in vivo. Postoperative pain induced by intramedullary fixation after tibial fracture was confirmed by decreased mechanical and thermal pain thresholds. Postoperative pain induced cognitive impairment, promoted axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus. Postoperative pain also increased pro-inflammatory factors, cyclin D1 and decreased anti-inflammatory factors in hippocampus. However, these changes were all reversed by morphine analgesia. Bioinformatics analysis identified the critical role of exosome miR-124-3p in cognitive impairment, which was confirmed to be down-regulated in hippocampus of postoperative pain mice. BV-2 microglia overexpressing exosome miR-124-3p showed decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. In vivo, stereotactic injection of exogenous miR-124-3p into hippocampus decreased pro-inflammatory factors, cyclin D1 and increased anti-inflammatory factors. The cognitive impairment, axon demyelination, decreased BDNF, NG and increased VILIP-1 expressions in hippocampus were all alleviated by exogenous exosome miR-124-3p. Microglial exosome miR-124-3p in hippocampus alleviates cognitive impairment induced by postoperative pain through microglia polarization in elderly mice.

Project description:As one of the most serious complications of sepsis, sepsis-associated encephalopathy has not been effectively treated or prevented. Exosomes, as a new therapeutic method, play a protective role in neurodegenerative diseases, stroke and traumatic brain injury in recent years. The purpose of this study was to investigate the role of exosomes in glutamate (Glu)-induced neuronal injury, and to explore its mechanism, providing new ideas for the treatment of sepsis-associated encephalopathy. The neuron damage model induced by Glu was established, and its metabolomics was analyzed and identified. BV2 cells were induced to differentiate into M1 and M2 subtypes. After the exosomes from both M1-BV2 cells and M2-BV2 cells were collected, exosome morphological identification was performed by transmission electron microscopy and exosome-specific markers were also detected. These exosomes were then cocultured with HT22 cells. CCK-8 method and LDH kit were used to detect cell viability and toxicity. Cell apoptosis, mitochondrial membrane potential and ROS content were respectively detected by flow cytometry, JC-1 assay and DCFH-DA assay. MiR-124-3p expression level was detected by qRT-PCR and Western blot. Bioinformatics analysis and luciferase reporter assay predicted and verified the relationship between miR-124-3p and ROCK1 or ROCK2. Through metabolomics, 81 different metabolites were found, including fructose, GABA, 2, 4-diaminobutyric acid, etc. The enrichment analysis of differential metabolites showed that they were mainly enriched in glutathione metabolism, glycine and serine metabolism, and urea cycle. M2 microglia-derived exosomes could reduce the apoptosis, decrease the accumulation of ROS, restore the mitochondrial membrane potential and the anti-oxidative stress ability in HT22 cells induced by Glu. It was also found that the protective effect of miR-124-3p mimic on neurons was comparable to that of M2-EXOs. Additionally, M2-EXOs might carry miR-124-3p to target ROCK1 and ROCK2 in neurons, affecting ROCK/PTEN/AKT/mTOR signaling pathway, and then reducing Glu-induced neuronal apoptosis. M2 microglia-derived exosomes may protect HT22 cells against Glu-induced injury by transferring miR-124-3p into HT22 cells, with ROCK being a target gene for miR-124-3p.

Dataset Information

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

Publications

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

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