{"title":"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。","authors":"Bingjin Liu, Qunfang Zhao, Qingqing Shi, Weiqi Xu, Fangxiao Shi, Ruhui Yang, Xinwen Zhou","doi":"10.1007/s12028-025-02293-2","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19118,"journal":{"name":"Neurocritical Care","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Hypothermia Alleviates TBI-Induced Tau Hyperphosphorylation Through RBM3-Dependent GSK-3β and AMPK Pathways.\",\"authors\":\"Bingjin Liu, Qunfang Zhao, Qingqing Shi, Weiqi Xu, Fangxiao Shi, Ruhui Yang, Xinwen Zhou\",\"doi\":\"10.1007/s12028-025-02293-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>\",\"PeriodicalId\":19118,\"journal\":{\"name\":\"Neurocritical Care\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2025-06-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurocritical Care\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s12028-025-02293-2\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurocritical Care","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12028-025-02293-2","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Hypothermia Alleviates TBI-Induced Tau Hyperphosphorylation Through RBM3-Dependent GSK-3β and AMPK Pathways.
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.
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.
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