Mechanisms of fibrinogen trans-activation of the EGFR/Ca2+ signaling axis to regulate mitochondrial transport and energy transfer and inhibit axonal regeneration following cerebral ischemia.

IF 3.2 3区 医学 Q2 CLINICAL NEUROLOGY Journal of Neuropathology and Experimental Neurology Pub Date : 2024-11-04 DOI:10.1093/jnen/nlae114
Shengqiang Zhou, Bo Li, Dahua Wu, Yanjun Chen, Wen Zeng, Jia Huang, Lingjuan Tan, Guo Mao, Fang Liu
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Abstract

Ischemic stroke results in inhibition of axonal regeneration but the roles of fibrinogen (Fg) in neuronal signaling and energy crises in experimental stroke are under-investigated. We explored the mechanism of Fg modulation of axonal regeneration and neuronal energy crisis after cerebral ischemia using a permanent middle cerebral artery occlusion (MCAO) rat model and primary cortical neurons under low glucose-low oxygen. Behavioral tests assessed neurological deficits; immunofluorescence, immunohistochemistry, and Western-blot analyzed Fg and protein levels. Fluo-3/AM fluorescence measured free Ca2+ and ATP levels were gauged via specific assays and F560nm/F510nm ratio calculations. Mito-Tracker Green labeled mitochondria and immunoprecipitation studied protein interactions. Our comprehensive study revealed that Fg inhibited axonal regeneration post-MCAO as indicated by reduced GAP43 expression along with elevated free Ca2+, both suggesting an energy crisis. Fg impeded mitochondrial function and mediated impairment through the EGFR/Ca2+ axis by trans-activating EGFR via integrin αvβ3 interaction. These results indicate that the binding of Fg with integrin αvβ3 leads to the trans-activation of the EGFR/Ca2+ signaling axis thereby disrupting mitochondrial energy transport and axonal regeneration and exacerbating the detrimental effects of ischemic neuronal injury.

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纤维蛋白原转激活表皮生长因子受体/Ca2+信号轴调节线粒体转运和能量转移并抑制脑缺血后轴突再生的机制。
缺血性中风会导致轴突再生受抑制,但纤维蛋白原(Fg)在实验性中风的神经元信号传导和能量危机中的作用还未得到充分研究。我们利用永久性大脑中动脉闭塞(MCAO)大鼠模型和低糖低氧条件下的原发性皮层神经元,探讨了 Fg 调节脑缺血后轴突再生和神经元能量危机的机制。行为测试评估了神经功能缺损情况;免疫荧光、免疫组织化学和 Western 印迹分析了 Fg 和蛋白质水平。Fluo-3/AM荧光测定游离Ca2+,并通过特定测定和F560nm/F510nm比值计算测量ATP水平。Mito-Tracker Green标记线粒体,免疫沉淀法研究蛋白质之间的相互作用。我们的综合研究显示,Fg抑制了MCAO后的轴突再生,表现为GAP43表达减少和游离Ca2+升高,两者都表明出现了能量危机。Fg通过整合素αvβ3相互作用反式激活表皮生长因子受体,从而阻碍线粒体功能,并通过表皮生长因子受体/Ca2+轴介导损伤。这些结果表明,Fg 与整合素 αvβ3 结合会导致表皮生长因子受体/Ca2+ 信号轴的反式激活,从而破坏线粒体能量运输和轴突再生,加剧缺血性神经元损伤的有害影响。
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来源期刊
CiteScore
5.40
自引率
6.20%
发文量
118
审稿时长
6-12 weeks
期刊介绍: Journal of Neuropathology & Experimental Neurology is the official journal of the American Association of Neuropathologists, Inc. (AANP). The journal publishes peer-reviewed studies on neuropathology and experimental neuroscience, book reviews, letters, and Association news, covering a broad spectrum of fields in basic neuroscience with an emphasis on human neurological diseases. It is written by and for neuropathologists, neurologists, neurosurgeons, pathologists, psychiatrists, and basic neuroscientists from around the world. Publication has been continuous since 1942.
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