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ZBP1 mediates the progression of Alzheimer's disease via pyroptosis by regulating IRF3

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Abstract

Alzheimer’s disease (AD) is one of the leading causes of death throughout the world. Z-DNA binding protein 1 (ZBP1), a DNA-related gene, is associated with inflammation, and its expression is altered in AD brain. We aimed to elucidate the exact role of ZBP1 in AD development and its potential regulatory mechanism. First, we constructed both in vivo and in vitro models of AD and investigated the ZBP1 expression profile. A loss-of-function assay was performed by transfecting lentivirus carrying ZBP1 short hairpin RNA (shRNA). By evaluating cell death, oxidative stress, inflammation response and pyroptosis, the function of ZBP1 was validated. Finally, the correlation between ZBP1 and interferon regulatory factor 3 (IRF3) was verified. We also performed rescue experiments to validate the crucial role of IRF3 in ZBP1-mediated AD progression. According to our results, ZBP1 was upregulated in AD rat tissue and AD neurons. Silencing ZBP1 dramatically decreased cell injury, oxidative stress and inflammation in AD neurons and improved the cognitive function of AD rats. Additionally, IRF3 expression and phosphorylation were significantly elevated during AD development and positively correlated with ZBP1. Taken together, silencing ZBP1 suppressed cell injury and pyroptosis of AD neurons and improved cognitive function of AD rats via inhibiting IRF3. These findings might provide a novel insight for AD target diagnosis and therapy.

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Data availability

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

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Acknowledgements

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Funding

This study was supported by the Key Research and Development Plan of Shaanxi Province (2023-YBSF-127).

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Authors and Affiliations

  1. Department of Neurology, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Xi’an, 710068, Shaanxi, China

    Hena Guo, Ruili Chen, Peng Li & Qian Yang

  2. Graduate School, Xi’an Medical University, Xi’an, China

    Yifan He

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  2. Ruili Chen
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Contributions

PL designed experiments, analyzed clinical samples. RC and QY performed testing and laboratory support. YH conducted data analysis. HG wrote and edited the manuscript. All authors adopt the publication of the final manuscript.

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Correspondence to Peng Li.

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Ethical approval

Our study got approval from the Animal Care and Use Ethical Committee of Shaanxi Provincial People’s Hospital. And all experimental utilizations of rats were conducted in line with the Health Guide for the Care and Use of Laboratory Animals (National Institutes).

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11010_2023_4702_MOESM1_ESM.tif

Fig.S1 Silencing RIF3 depressed Aβ-induced cell injury and oxidative stress in neurons.shRNAs (50 nM) were transfected into hippocampal neurons for 48 h. After that, 20 µmol/L Aβ was used to treat cells for 48 h. (A and B) The expression levels of IRF3 mRNA and protein were evaluated using RT-qPCR and western blotting. (C and D) MTT and flow cytometry were performed to determine cell viability and apoptosis. (E-I) Commercial kits were utilized to measure the contents and activities of MDA, SOD, ROS, CAT and GSH. ** P < 0.01; N.S.: no significance.

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Guo, H., Chen, R., Li, P. et al. ZBP1 mediates the progression of Alzheimer's disease via pyroptosis by regulating IRF3. Mol Cell Biochem 478, 2849–2860 (2023). https://doi.org/10.1007/s11010-023-04702-6

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  • DOI: https://doi.org/10.1007/s11010-023-04702-6

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