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Kapβ2 Inhibits Perioperative Neurocognitive Disorders in Rats with Mild Cognitive Impairment by Reversing the Nuclear-Cytoplasmic Mislocalization of hnRNPA2/B1

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Abstract    

Harmful stimuli trigger mutations lead to uncontrolled accumulation of hnRNPA2/B1 in the cytoplasm, exacerbating neuronal damage. Kapβ2 mediates the bidirectional transport of most substances between the cytoplasm and the nucleus. Kapβ2 guides hnRNPA2/B1 back into the nucleus and restores its function, alleviating related protein toxicity. Here, we aim to explore the involvement of Kapβ2 in neurodegeneration in rats with MCI following sevoflurane anesthesia and surgery. Firstly, novel object recognition test and Barnes maze were conducted to assess behavioral performances, and we found Kapβ2 positively regulated the recovery of memory and cognitive function. In vivo electrophysiological experiments revealed that the hippocampal theta rhythm energy distribution was disrupted, coherence was reduced, and long-term potentiation was attenuated in MCI rats. LTP was greatly improved with positive modulation of Kapβ2. Next, functional MRI and BOLD imaging will be employed to examine the AFLL and FC values of dynamic connectivity between the cortex and hippocampus of the brain. The findings show that regulating Kapβ2 in the hippocampus region enhances functional activity and connections between brain regions in MCI rats. WB results showed that increasing Kapβ2 expression improved the expression and recovery of cognitive-related proteins in the hippocampus of MCI rats. Finally, WB and immunofluorescence were used to examine the changes in hnRNPA2/B1 expression in the nucleus and cytoplasm after overexpression of Kapβ2, and it was found that nucleocytoplasmic mis location was alleviated. Overall, these data show that Kapβ2 reverses the nucleoplasmic misalignment of hnRNPA2/B1, which slows neurodegeneration towards dementia in MCI after sevoflurane anesthesia and surgery. Our findings may lead to new approaches for perioperative neuroprotection of MCI patients.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to express my gratitude to all these who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82071220, 82371205), Natural Science Foundation of Tianjin (20JCYBJC01290), and the Science and Technology Foundation of Tianjin Health Commission (MS20013), and Tianjin key Medical Discipline (Specialty) Construction Project (TJYXZDXK-072C), Tianjin Multiple Investment Foundation of Applied Basic Research (21JCQNJC01020), Tianjin Health Research Project (TJWJ2023XK019, TJWJ2023QN042).

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  1. Miao Zhang, Feiyu Jia and Qiang Wang contributed equally to this work.

Authors and Affiliations

  1. The Third Central Clinical College of Tianjin Medical University, Tianjin, China

    Miao Zhang, Feiyu Jia, Qiang Wang & Haiyun Wang

  2. Nankai University Affinity the Third Central Hospital, Tianjin, China

    Miao Zhang, Feiyu Jia, Qiang Wang, Chenyi Yang, Xinyi Wang, Tianyue Liu, Qingkai Tang & Haiyun Wang

  3. Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Artificial Cell Engineering Technology Research Center, Tianjin Institute of Hepatobiliary Disease, Tianjin Third Central Hospital, Tianjin, China

    Miao Zhang, Feiyu Jia, Qiang Wang & Haiyun Wang

  4. College of Medicine, Nankai University, Tianjin, China

    Zhuo Yang

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Guarantor of integrity of the entire study: Miao Zhang, Haiyun Wang; study concepts: Miao Zhang, Haiyun Wang; study design: Miao Zhang; definition of intellectual content: Qiang Wang, Miao Zhang, Qingkai Tang; literature research: Feiyu Jia, Miao Zhang, Xinyi Wang; experimental studies: Feiyu Jia, Miao Zhang; data acquisition: Feiyu Jia, Miao Zhang, Tianyue Liu; data analysis: Miao Zhang, Qiang Wang; statistical analysis: Miao Zhang, Feiyu Jia, Chenyi Yang; manuscript preparation: Miao Zhang, Feiyu Jia, Qiang Wang; manuscript editing: Zhuo Yang; manuscript review: Haiyun Wang; All the authors approved for the final version.

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Correspondence to Zhuo Yang or Haiyun Wang.

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Zhang, M., Jia, F., Wang, Q. et al. Kapβ2 Inhibits Perioperative Neurocognitive Disorders in Rats with Mild Cognitive Impairment by Reversing the Nuclear-Cytoplasmic Mislocalization of hnRNPA2/B1. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03789-8

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