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Age-related p53 SUMOylation accelerates senescence and tau pathology in Alzheimer’s disease

Cell Death & Differentiation volume 32, pages 837–854 (2025)Cite this article

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Abstract

Aging is a major risk factor for Alzheimer’s disease (AD). With the prevalence of AD increased, a mechanistic linkage between aging and the pathogenesis of AD needs to be further addressed. Here, we report that a small ubiquitin-related modifier (SUMO) modification of p53 is implicated in the process which remarkably increased in AD patient’s brain. Mechanistically, SUMOylation of p53 at K386 residue causes the dissociation of SET/p53 complex, thus releasing SET into the cytoplasm, SET further interacts with cytoplasmic PP2A and inhibits its activity, resulting in tau hyperphosphorylation in neurons. In addition, SUMOylation of p53 promotes the p53 Ser15 phosphorylation that mediates neuronal senescence. Notably, p53 SUMOylation contributes to synaptic damage and cognitive defects in AD model mice. We also demonstrate that the SUMOylation inhibiter, Ginkgolic acid, recovering several senescent phenotypes drove by p53 SUMOylation in primary neurons. These findings suggest a previously undiscovered etiopathogenic relationship between aging and AD that is linked to p53 SUMOylation and the potential of SUMOylated p53-based therapeutics for neurodegeneration such as Alzheimer’s disease.

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Fig. 1: p53 SUMOylation was upregulated in the hippocampi of aged mice and in human AD brains.
Fig. 2: Down-regulation of p53 SUMOylation alleviated cell senescence and tau hyperphosphorylation.
Fig. 3: p53 SUMOylation promoted its dissociation with SET and induced SET cytoplasmic retention.
Fig. 4: p53 SUMOylation aggravated the hippocampus-dependent cognitive impairments and neuronal senescence in AD transgenic mice.
Fig. 5: Down-regulation of p53 SUMOylation alleviated the synaptic damage in AD transgenic mice brains.
Fig. 6: p53 SUMOylation intensified the hippocampus-dependent cognitive defects and proinflammatory SASP in SAMP8 mice.
Fig. 7: Inhibition of p53 SUMOylation by Ginkgolic acid mitigated neuronal senescence and tau hyperphosphorylation.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or Supplementary Materials. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported in parts by grants from the National Natural Science Foundation of China (82330041, 92049107), a grant from Science and Technology Innovation Team project to Xiaochuan Wang from the Department of Science and Technology of Hubei Province (2022-72-18). The authors are grateful to Mr. Dan Ke and Ms. Qun Wang for helpful technical suggestions during the conduct of this study.

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  1. These authors contributed equally: Lu Wan, Fumin Yang.

Authors and Affiliations

  1. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Lu Wan, Fumin Yang, Anqi Yin, Yong Luo, Yi Liu, Jian-Zhi Wang, Rong Liu & Xiaochuan Wang

  2. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China

    Fei Liu, Jian-Zhi Wang & Xiaochuan Wang

  3. Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

    Fei Liu

  4. Hubei Key Laboratory of Cognitive and Affective Disorders, Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China

    Jian-Zhi Wang & Xiaochuan Wang

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Contributions

XW conceived the project, designed all experiments, and organized the results. LW and FY planned and performed most of the experiments and organized the results. AY, YL, and YL prepared primary neurons and animal experiments. FL, J-ZW, and RL assisted with data analysis and interpretation and critically read the manuscript. All of the authors were involved in analyzing the data and contributed to manuscript discussion and editing.

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Correspondence to Xiaochuan Wang.

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Animal experiments and manipulation were approved by the Ethics Committee of the Animal Experiment Center, Tongji Medical College, Huazhong University of Science and Technology.

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Wan, L., Yang, F., Yin, A. et al. Age-related p53 SUMOylation accelerates senescence and tau pathology in Alzheimer’s disease. Cell Death Differ 32, 837–854 (2025). https://doi.org/10.1038/s41418-025-01448-0

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