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Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI.
Molecular Therapy ( IF 12.1 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.ymthe.2019.11.017
Xintong Ge 1 , Mengtian Guo 2 , Tianpeng Hu 2 , Wenzhu Li 2 , Shan Huang 2 , Zhenyu Yin 2 , Ying Li 3 , Fanglian Chen 3 , Luoyun Zhu 4 , Chunsheng Kang 3 , Rongcai Jiang 1 , Ping Lei 2 , Jianning Zhang 1
Affiliation  

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.

中文翻译:

rmTBI后小胶质细胞外泌体miR-124-3p的增加减轻了神经变性并改善了认知结果。

重复性轻度颅脑外伤(rmTBI)被认为是长期神经退行性疾病(例如阿尔茨海默氏病)的重要危险因素,该疾病的特征是β淀粉样蛋白异常和认知功能受损。据报道,小胶质外泌体参与了阿尔茨海默氏病中β-淀粉样蛋白的运输,分布和清除。但是,它们对rmTBI后神经退行性发展的影响尚不清楚。在本研究中,研究了miRNA在小胶质外泌体中调节创伤后神经变性的作用。我们证明,rmTBI后,在急性,亚急性和慢性期,来自受伤脑部的小胶质外泌体中的miR-124-3p水平显着改变。在体外实验中 miR-124-3p(EXO-124)上调的小胶质外泌体减轻了重复性划痕损伤神经元的神经变性。通过靶向Rela的miR-124-3p发挥了这种作用,Rela是ApoE的抑制性转录因子,可促进β-淀粉样蛋白水解分解,从而抑制β-淀粉样蛋白异常。在患有rmTBI的小鼠中,静脉注射的小胶质外泌体被受伤的大脑中的神经元吸收。此外,通过靶向Rela / ApoE信号通路,将外泌体中的miR-124-3p转移到海马神经元中并减轻神经变性。因此,EXO-124治疗改善了rmTBI后的认知结局,为将来的临床翻译提供了一种有希望的治疗策略。通过靶向Rela的miR-124-3p发挥了这种作用,Rela是ApoE的抑制性转录因子,可促进β-淀粉样蛋白水解分解,从而抑制β-淀粉样蛋白异常。在患有rmTBI的小鼠中,静脉注射的小胶质外泌体被受伤的大脑中的神经元吸收。此外,通过靶向Rela / ApoE信号通路,将外泌体中的miR-124-3p转移到海马神经元中并减轻神经变性。因此,EXO-124治疗改善了rmTBI后的认知结局,为将来的临床翻译提供了一种有希望的治疗策略。通过靶向Rela的miR-124-3p发挥了这种作用,Rela是ApoE的抑制性转录因子,可促进β-淀粉样蛋白水解分解,从而抑制β-淀粉样蛋白异常。在患有rmTBI的小鼠中,静脉注射的小胶质外泌体被受伤的大脑中的神经元吸收。此外,通过靶向Rela / ApoE信号通路,将外泌体中的miR-124-3p转移到海马神经元中并减轻神经变性。因此,EXO-124治疗改善了rmTBI后的认知结局,为将来的临床翻译提供了一种有希望的治疗策略。静脉注射的小胶质外泌体被受伤的大脑中的神经元吸收。此外,通过靶向Rela / ApoE信号通路,将外泌体中的miR-124-3p转移到海马神经元中并减轻神经变性。因此,EXO-124治疗改善了rmTBI后的认知结局,为将来的临床翻译提供了一种有希望的治疗策略。静脉注射的小胶质外泌体被受伤的大脑中的神经元吸收。此外,通过靶向Rela / ApoE信号通路,将外泌体中的miR-124-3p转移到海马神经元中并减轻神经变性。因此,EXO-124治疗改善了rmTBI后的认知结局,为将来的临床翻译提供了一种有希望的治疗策略。
更新日期:2019-11-28
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