Kapβ2通过解决轻度认知障碍大鼠模型中的HnRNPA2/B1纤维缠结来减轻麻醉后神经认知功能障碍。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology Pub Date : 2025-08-12 DOI:10.1016/j.expneurol.2025.115426

Miao Zhang , Xinyi Wang , Chenyi Yang , Zixuan Wang , Huihui Liao , Lin Zhang , Xi Xin , Haiyun Wang

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引用次数: 0

摘要

背景：术前轻度认知障碍（MCI）患者围手术期神经认知障碍（PND）的发生率高于无MCI患者，且进展为痴呆的比率较高；然而，潜在的机制尚不清楚。异质核核糖核蛋白A2/B1 （hnRNPA2/B1）是一种rna结合蛋白（RBP），通过立体拉链基序形成原纤维缠结。HnRNPA2/B1异常积累与局部神经变性和认知障碍密切相关。而核丝蛋白-β2 （Kapβ2）作为核输入受体，能够特异性识别hnRNPA2/B1，减轻其在细胞质中蓄积所引起的神经毒性。方法:为了探讨hnRNPA2/B1在PND中的作用以及Kapβ2的过表达是否会减少hnRNPA2/B1纤维缠结的形成，本研究采用Morris水迷宫（MWM）方法，比较了不同麻醉（3 %七氟醚、40 mg/kg/h异丙酚和9 %地氟醚）对MCI大鼠胫骨骨折切开复位内固定（ORIF）后PND的发生率、海马微观结构的完整性以及hnRNPA2/B1在MCI模型中的分布和功能。脑磁共振弥散张量成像（DTI）、免疫荧光染色、RT-qPCR和western blot。同时，为了评估Kapβ2对七氟醚+手术后认知功能的影响，在PND最严重模型大鼠海马立体定向注射过表达Kapβ2的腺相关病毒。结果：七氟醚诱导严重hnRNPA2/B1纤维缠结和认知能力下降。Kapβ2过表达减少细胞质hnRNPA2/B1积累，减轻认知障碍。结论：本研究揭示了手术中使用麻醉诱导hnRNPA2/B1胞浆原纤维缠结促进MCI大鼠PND发生的病理机制，并通过Kapβ2的过表达恢复hnRNPA2/B1的核定位和神经元功能，为高危转化为痴呆的MCI患者围手术期神经保护和康复提供了新的思路。

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Kapβ2 attenuates post-anesthetic neurocognitive dysfunction by resolving HnRNPA2/B1 fibrillary tangles in a rat model of mild cognitive impairment

Background

Patients with mild cognitive impairment (MCI) before surgery have a higher incidence of perioperative neurocognitive disorders (PND) and a higher rate of progression to dementia than those without MCI; however, the underlying mechanisms are unclear. Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is an RNA-binding protein (RBP) that forms fibrillary tangles via a steric zipper motif. Abnormal accumulation of HnRNPA2/B1 is strongly correlated with local neurodegeneration and cognitive impairment. However, karyopherin-β2 (Kapβ2), a nuclear import receptor, can specifically recognize hnRNPA2/B1 and alleviate the neurotoxicity caused by its accumulation in the cytoplasm.

Methods

In this study, to explore the role of hnRNPA2/B1 in PND and whether overexpression of Kapβ2 reduces hnRNPA2/B1 fibrillary tangle formation, we compared different anesthetics (3 % sevoflurane, 40 mg/kg/h propofol, and 9 % desflurane) to the incidence of PND, the integrity of hippocampal microstructure, as well as the distribution and function of hnRNPA2/B1 in a rat model of MCI after open reduction and internal fixation (ORIF) of tibial fractures by using Morris water maze (MWM), brain magnetic resonance diffusion tensor imaging (DTI), immunofluorescence staining, RT-qPCR, and western blot. Simultaneously, to assess the effect of Kapβ2 on cognitive function after sevoflurane+surgery, the most severe model for PND, Kapβ2 overexpressing adeno-associated virus was stereotactically injected in the hippocampus of rats.

Results

Sevoflurane induced severe hnRNPA2/B1 fibrillary tangles and cognitive decline. Kapβ2 overexpression reduced cytoplasmic hnRNPA2/B1 accumulation and attenuated cognitive impairment.

Conclusions

This study revealed the pathological mechanism of hnRNPA2/B1 cytoplasmic fibrillary tangle induced by anesthesia used in surgery to promote the occurrence of PND in MCI rats and restored the nuclear localization of hnRNPA2/B1 and neuronal function through the overexpression of Kapβ2, which provides a new idea for perioperative neuroprotection and rehabilitation in patients with MCI who have a high risk of conversion to dementia.

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来源期刊

Experimental Neurology 医学-神经科学

CiteScore

10.10

自引率

3.80%

发文量

258

审稿时长

42 days

期刊介绍： Experimental Neurology, a Journal of Neuroscience Research, publishes original research in neuroscience with a particular emphasis on novel findings in neural development, regeneration, plasticity and transplantation. The journal has focused on research concerning basic mechanisms underlying neurological disorders.