Decreased cold-inducible RNA-binding protein (CIRP) binding to GluRl on neuronal membranes mediates memory impairment resulting from prolonged hypobaric hypoxia exposure

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2024-09-24 DOI:10.1111/cns.70059

Hui Jiang, Chenyan Lu, Haoyang Wu, Jie Ding, Jiayan Li, Jianfeng Ding, Yuqi Gao, Guohua Wang, Qianqian Luo

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Abstract

Aim

To investigate the molecular mechanisms underlying memory impairment induced by high-altitude (HA) hypoxia, specifically focusing on the role of cold-inducible RNA-binding protein (CIRP) in regulating the AMPA receptor subunit GluR1 and its potential as a therapeutic target.

Methods

A mouse model was exposed to 14 days of hypobaric hypoxia (HH), simulating conditions at an altitude of 6000 m. Behavioral tests were conducted to evaluate memory function. The expression, distribution, and interaction of CIRP with GluR1 in neuronal cells were analyzed. The binding of CIRP to GluR1 mRNA and its impact on GluR1 protein expression were examined. Additionally, the role of CIRP in GluR1 regulation was assessed using Cirp knockout mice. The efficacy of the Tat-C16 peptide, which consists of the Tat sequence combined with the CIRP 110-125 amino acid sequence, was also tested for its ability to mitigate HH-induced memory decline.

Results

CIRP was primarily localized in neurons, with its expression significantly reduced following HH exposure. This reduction was associated with decreased GluR1 protein expression on the cell membrane and increased localization in the cytoplasm. The interaction between CIRP and GluR1 was diminished under HH conditions, leading to reduced GluR1 stability on the cell membrane and increased cytoplasmic relocation. These changes resulted in a decreased number of synapses and dendritic spines, impairing learning and memory functions. Administration of the Tat-C16 peptide effectively ameliorated these impairments by modulating GluR1 expression and distribution in HH-exposed mice.

Conclusion

CIRP plays a critical role in maintaining synaptic integrity under hypoxic conditions by regulating GluR1 expression and distribution. The Tat-C16 peptide shows promise as a therapeutic strategy for alleviating cognitive decline associated with HA hypoxia.

Abstract Image

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冷诱导 RNA 结合蛋白（CIRP）与神经元膜上的 GluRl 结合减少介导了长时间低压氧暴露导致的记忆损伤。

目的：研究高海拔缺氧诱导记忆损伤的分子机制，特别关注冷诱导RNA结合蛋白（CIRP）在调节AMPA受体亚基GluR1中的作用及其作为治疗靶点的潜力：方法：模拟海拔 6000 米的环境，对小鼠模型进行为期 14 天的低压缺氧（HH）。进行行为测试以评估记忆功能。分析了神经元细胞中 CIRP 的表达、分布以及与 GluR1 的相互作用。研究了 CIRP 与 GluR1 mRNA 的结合及其对 GluR1 蛋白表达的影响。此外，还利用 Cirp 基因敲除小鼠评估了 CIRP 在 GluR1 调节中的作用。此外，还测试了由 Tat 序列和 CIRP 110-125 氨基酸序列组成的 Tat-C16 肽对缓解 HH 诱导的记忆衰退的功效：结果：CIRP主要定位于神经元，其表达在暴露于HH后显著减少。这种减少与细胞膜上 GluR1 蛋白表达的减少和细胞质中定位的增加有关。在 HH 条件下，CIRP 与 GluR1 之间的相互作用减弱，导致 GluR1 在细胞膜上的稳定性降低，而在细胞质中的定位增加。这些变化导致突触和树突棘数量减少，从而损害了学习和记忆功能。通过调节 GluR1 在暴露于 HH 的小鼠中的表达和分布，服用 Tat-C16 肽可有效改善这些损伤：结论：CIRP 通过调节 GluR1 的表达和分布，在缺氧条件下维持突触完整性方面发挥着关键作用。Tat-C16肽有望成为缓解与HA缺氧相关的认知能力下降的治疗策略。

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

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.