Hypothermia Alleviates TBI-Induced Tau Hyperphosphorylation Through RBM3-Dependent GSK-3β and AMPK Pathways.

IF 3.6 3区医学 Q2 CLINICAL NEUROLOGY

Neurocritical Care Pub Date : 2025-06-02 DOI:10.1007/s12028-025-02293-2

Bingjin Liu, Qunfang Zhao, Qingqing Shi, Weiqi Xu, Fangxiao Shi, Ruhui Yang, Xinwen Zhou

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引用次数: 0

Abstract

Background: Traumatic brain injury (TBI) often results in tau hyperphosphorylation, a key pathological feature of neurodegenerative diseases such as Alzheimer's disease. Hypothermia (HT) is a promising therapeutic intervention for TBI, but the underlying molecular mechanisms remain unclear. This study investigates the role of RNA-binding motif protein 3 (RBM3) in mediating the neuroprotective effects of HT on tau phosphorylation and its involvement in glycogen synthase kinase 3 beta (GSK-3β) and AMP-activated protein kinase (AMPK) signaling.

Methods: We used a TBI mouse model to assess the effects of HT on tau phosphorylation using Western blotting and immunohistochemistry. The phosphorylation status of GSK-3β (Ser9) and AMPK (Thr172) was also analyzed to explore key signaling pathways. RBM3 expression was modulated using RBM3 short hairpin RNA (knockdown) and adenovirus-RBM3 plasmid (overexpression) to determine its role in HT-induced changes in tau phosphorylation.

Results: Hypothermia treatment significantly reduced tau hyperphosphorylation in TBI mice compared with controls. Western blotting revealed a significant increase in GSK-3β Ser9 phosphorylation (p < 0.01) and AMPK Thr172 phosphorylation (p < 0.05) in the HT group. Manipulation of RBM3 expression showed that both RBM3 knockdown and overexpression affected the extent of tau dephosphorylation mediated by HT. Specifically, RBM3 overexpression enhanced the protective effects of HT, whereas knockdown diminished its efficacy.

Conclusions: Our findings suggest that RBM3 is a crucial mediator of the neuroprotective effects of hypothermia in TBI, acting through modulation of GSK-3β and AMPK signaling pathways. These results provide new insights into the molecular mechanisms of TBI treatment and highlight RBM3 as a potential therapeutic target for neurodegenerative diseases associated with tauopathies. Limitations include the need for further validation in clinical models.

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低温通过rbm3依赖性GSK-3β和AMPK通路减轻tbi诱导的Tau过度磷酸化。

背景：创伤性脑损伤（TBI）经常导致tau蛋白过度磷酸化，这是阿尔茨海默病等神经退行性疾病的一个关键病理特征。低温治疗（HT）是一种很有前途的治疗方法，但其潜在的分子机制尚不清楚。本研究探讨了rna结合基序蛋白3 （RBM3）在介导HT对tau磷酸化的神经保护作用及其参与糖原合成酶激酶3β (GSK-3β)和amp活化蛋白激酶（AMPK）信号传导中的作用。方法：采用Western blotting和免疫组织化学方法，建立脑外伤小鼠模型，观察HT对tau蛋白磷酸化的影响。我们还分析了GSK-3β (Ser9)和AMPK （Thr172）的磷酸化状态，以探索关键的信号通路。利用RBM3短发夹RNA（敲低）和腺病毒-RBM3质粒（过表达）调节RBM3的表达，以确定其在ht诱导的tau磷酸化变化中的作用。结果：与对照组相比，低温治疗显著降低了TBI小鼠的tau过度磷酸化。结论：我们的研究结果表明RBM3是低温对TBI患者神经保护作用的重要介质，通过调节GSK-3β和AMPK信号通路起作用。这些结果为TBI治疗的分子机制提供了新的见解，并突出了RBM3作为与tau病相关的神经退行性疾病的潜在治疗靶点。局限性包括需要在临床模型中进一步验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurocritical Care 医学-临床神经学

CiteScore

7.40

自引率

8.60%

发文量

221

审稿时长

4-8 weeks

期刊介绍： Neurocritical Care is a peer reviewed scientific publication whose major goal is to disseminate new knowledge on all aspects of acute neurological care. It is directed towards neurosurgeons, neuro-intensivists, neurologists, anesthesiologists, emergency physicians, and critical care nurses treating patients with urgent neurologic disorders. These are conditions that may potentially evolve rapidly and could need immediate medical or surgical intervention. Neurocritical Care provides a comprehensive overview of current developments in intensive care neurology, neurosurgery and neuroanesthesia and includes information about new therapeutic avenues and technological innovations. Neurocritical Care is the official journal of the Neurocritical Care Society.