Deciphering the CREB-NR2B axis: Unraveling the crosstalk of insulin and TGF-β signalling in ameliorating postoperative cognitive dysfunction

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-06-01 Epub Date: 2025-03-22 DOI:10.1016/j.lfs.2025.123574

Jiawen Zhou , Xue Han , Ziqi Wei , Yujia Liu , Jiyan Xu , Minhui Xu , Tianjiao Xia , Xiaolei Cheng , Xiaoping Gu

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Abstract

Postoperative cognitive dysfunction (POCD) is a significant postoperative complication, particularly in the elderly, linked to inflammation-mediated neural dysfunction. Insulin resistance and disruptions in transforming growth factor beta (TGF-β) signalling are associated with cognitive decline in aging, yet their roles in POCD are not fully understood. Here, we demonstrated that both insulin and TGF-β pathways were disrupted in POCD mouse models, with recombinant insulin and TGF-β treatments improving cognitive outcomes. These treatments reversed neuroinflammation in vitro, while CREB knockdown abrogated the protective effects, both in vivo and in vitro. Mechanistically, CREB was found to mediate the protective effects of insulin and TGF-β in POCD by directly regulating the expression of the cognitive-related protein NR2B. Altogether, our study identifies a key molecular target involved in the critical signalling pathways associated with POCD, offering promising therapeutic strategies for prevention and treatment.

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破译CREB-NR2B轴：揭示胰岛素和tgf-β信号传导在改善术后认知功能障碍中的串扰。

术后认知功能障碍（POCD）是一种重要的术后并发症，特别是在老年人中，与炎症介导的神经功能障碍有关。胰岛素抵抗和转化生长因子β (TGF-β)信号的中断与衰老过程中的认知能力下降有关，但它们在POCD中的作用尚不完全清楚。在这里，我们证明了胰岛素和TGF-β通路在POCD小鼠模型中都被破坏，重组胰岛素和TGF-β治疗改善了认知结果。这些治疗在体外逆转了神经炎症，而CREB敲除在体内和体外都取消了保护作用。机制上，发现CREB通过直接调节认知相关蛋白NR2B的表达，介导胰岛素和TGF-β对POCD的保护作用。总之，我们的研究确定了一个与POCD相关的关键信号通路相关的关键分子靶点，为预防和治疗提供了有希望的治疗策略。

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

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.