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Navβ2 Intracellular Fragments Contribute to Aβ1-42-Induced Cognitive Impairment and Synaptic Deficit Through Transcriptional Suppression of BDNF

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Abstract

A pathological hallmark of Alzheimer’s disease (AD) is the region-specific accumulation of the amyloid-beta protein (Aβ), which triggers aberrant neuronal excitability, synaptic impairment, and progressive cognitive decline. Previous works have demonstrated that Aβ pathology induced aberrant elevation in the levels and excessive enzymatic hydrolysis of voltage-gated sodium channel type 2 beta subunit (Navβ2) in the brain of AD models, accompanied by alteration in excitability of hippocampal neurons, synaptic deficits, and subsequently, cognitive dysfunction. However, the mechanism is unclear. In this research, by employing cell models treated with toxic Aβ1-42 and AD mice, the possible effects and potential mechanisms induced by Navβ2. The results reveal that Aβ1-42 induces remarkable increases in Navβ2 intracellular domain (Navβ2-ICD) and decreases in both BDNF exons and protein levels, as well as phosphorylated tropomyosin-related kinase B (pTrkB) expression in cells and mice, coupled with cognitive impairments, synaptic deficits, and aberrant neuronal excitability. Administration with exogenous Navβ2-ICD further enhances these effects induced by Aβ1-42, while interfering the generation of Navβ2-ICD and/or complementing BDNF neutralize the Navβ2-ICD-conducted effects. Luciferase reporter assay verifies that Navβ2-ICD regulates BDNF transcription and expression by targeting its promoter. Collectively, our findings partially elucidate that abnormal enzymatic hydrolysis of Navβ2 induced by Aβ1-42-associated AD pathology leads to intracellular Navβ2-ICD overload, which may responsible to abnormal neuronal excitability, synaptic deficit, and cognition dysfunction, through its transcriptional suppression on BDNF. Therefore, this work supplies novel evidences that Navβ2 plays crucial roles in the occurrence and progression of cognitive impairment of AD by transcriptional regulatory activity of its cleaved ICD.

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Data Availability

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

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Acknowledgements

We thank other members of our laboratories and the funding bodies for their support to this work.

Funding

This work was supported by the Yunnan Fundamental Research Projects (grant no. 202201AT070295), the Special Fund of the Applied Basic Research Programs of Yunnan Province associated with Kunming Medical University in China (grant no. 202101AY070001-005), and National Natural Science Foundation of China (grant numbers 81960210 and 82371468).

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  1. Min-Nan Lu and Dan Wang contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuroscience, Kunming Medical University, Kunming, 650500, Yunnan, China

    Min-Nan Lu, Dan Wang, Chen-Jun Ye, Guo-Ji Yan, **n-Ying Shi, Li-Na Liu, Hui-**ang Zhang, **ao-Han Dong & Yan-Bin **yang

  2. Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, 650500, Yunnan, China

    Min-Nan Lu

  3. School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, 650500, Yunnan, China

    **g-Feng Song

  4. Experimental Teaching Center, Basic Medical College, Kunming Medical University, Kunming, 650500, Yunnan, China

    Shan-Shan Li

  5. Department of Laboratory Medicine, The Third People’s Hospital of Yunnan Province, Kunming, 650000, Yunnan, China

    Tao Hu

  6. Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Xu-Yang Wang

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  1. Min-Nan Lu
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All authors contributed to the study conception and design. Conceptualization: Min-Nan Lu, Dan Wang, Hui-**ang Zhang, Guo-Ji Yan, **ao-Han Dong, and Yan-Bin **yang. Data curation: Min-Nan Lu, Dan Wang, Chen-Jun Ye, **g-Feng Song, **n-Ying Shi, and Tao Hu. Formal analysis and investigation: **ao-Han Dong, Chen-Jun Ye, **g-Feng Song, and Xu-Yang Wang. Methodology: **ao-Han Dong, **n-Ying Shi, Tao Hu, and Shan-Shan Li. Project administration: Yan-Bin **yang. Supervision: Yan-Bin **yang and Min-Nan Lu. Validation and visualization: Dan Wang, Guo-Ji Yan, Chen-Jun Ye, and Yan-Bin **yang. Writing—original draft: Min-Nan Lu, Dan Wang, and Yan-Bin **yang. Writing—review and editing: Yan-Bin **yang and Li-Na Liu. Funding acquisition: Yan-Bin **yang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yan-Bin **yang.

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All animal experiments were conducted in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health and the Care and Use of Experimental Animals Guidelines formulated by the Ministry of Medicine of Yunnan, China. The Ethics Committee of Kunming Medical University approved the study protocol (permit no. Kmmu2020240; Kunming, China).

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Lu, MN., Wang, D., Ye, CJ. et al. Navβ2 Intracellular Fragments Contribute to Aβ1-42-Induced Cognitive Impairment and Synaptic Deficit Through Transcriptional Suppression of BDNF. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04317-y

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