Liu Bingjin, Zhao Qunfang, Shi Qingqing, Xu Weiqi, Shi Fangxiao, Yang Ruhui, Zhou Xinwen
New Dosage Form and Pharmacology Research Institute, School of Medicine and Pharmaceutical Engineering, Taizhou Vocational and Technical College, Taizhou, China.
Taizhou Vocational and Technical College, Taizhou, China.
Neurocrit Care. 2025 Jun 2. doi: 10.1007/s12028-025-02293-2.
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.
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.
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.
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.
创伤性脑损伤（TBI）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关键病理特征。低温治疗（HT）是一种有前景的TBI治疗干预措施，但其潜在分子机制仍不清楚。本研究调查了RNA结合基序蛋白3（RBM3）在介导HT对tau蛋白磷酸化的神经保护作用中的作用及其在糖原合酶激酶3β（GSK-3β）和AMP激活蛋白激酶（AMPK）信号传导中的参与情况。
我们使用TBI小鼠模型，通过蛋白质免疫印迹法和免疫组织化学评估HT对tau蛋白磷酸化的影响。还分析了GSK-3β（Ser9）和AMPK（Thr172）的磷酸化状态，以探索关键信号通路。使用RBM3短发夹RNA（敲低）和腺病毒-RBM3质粒（过表达）调节RBM3表达，以确定其在HT诱导的tau蛋白磷酸化变化中的作用。
与对照组相比，低温治疗显著降低了TBI小鼠的tau蛋白过度磷酸化。蛋白质免疫印迹法显示，HT组中GSK-3β Ser9磷酸化（p < 0.01）和AMPK Thr172磷酸化（p < 0.05）显著增加。对RBM3表达的操作表明，RBM3敲低和过表达均影响HT介导的tau蛋白去磷酸化程度。具体而言，RBM3过表达增强了HT的保护作用，而敲低则降低了其疗效。
我们的研究结果表明，RBM3是低温在TBI中神经保护作用的关键介质，通过调节GSK-3β和AMPK信号通路发挥作用。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蛋白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。
