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Phosphorylation of Truncated Tau Promotes Abnormal Native Tau Pathology and Neurodegeneration

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Abstract

Abnormal posttranslational modifications of tau play important roles in mediating neurodegeneration in tauopathies including Alzheimer’s disease. Both phosphorylation and truncation are implicated in the pathogenesis of tauopathies. However, whether phosphorylation aggravates truncated tau-induced pathology and neurodegeneration remains elusive. Here, we construct different tau fragments cleaved by delta secretase, with either phosphorylation or non-phosphorylation mimic mutations, and evaluate the contributions of phosphorylation to truncated tau-induced pathological and behavioral alterations in vitro and in vivo through biochemical methods including detergent insoluble tau extraction, western blot, immunofluorescence, flow cytometry, and behavior tests. Our results show that the self-aggregation of phospho-truncated tau is significantly influenced by the domain it contains. N-terminal inhibits, proline-rich domain promotes, and C-terminus have no impact on phospho-truncated tau aggregation. Phosphorylation of truncated tau1-368, which contains the microtubule-binding repeat domain and the proline-rich domain, induces endogenous tau phosphorylation and aggregation. In vivo, phospho-tau1-368 but not non-phospho-tau1-368 leads to a decrease in body weight of C57BL/6 J mice. Intriguingly, although tau1-368-induced anxiety behavior in C57BL/6 J mice is phosphorylation-independent, the recognition memory of mice is impaired by phospho-tau1-368, but not by non-phospho-tau1-368. Immunofluorescence staining shows that overexpressing phospho-tau1-368 results in neuronal loss and gliosis in the hippocampus, while the transmission of tau1-368 is phosphorylation-independent as revealed by the flow cytometry results in vitro and immunofluorescence staining in vivo. Our findings indicate that phosphorylation of truncated tau significantly fosters endogenous tau pathology and neurodegeneration.

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Acknowledgements

The authors thank the Medical Subcenter of HUST Analytical & Testing Center for data acquisition.

Funding

This work was supported by grants from the National Natural Science Foundation of China (31929002, 82071440, and 92049107), grants from the Innovative Research Groups of the National Natural Science Foundation of China (81721005), Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20210324141405014), Guangdong Basic and Applied Basic Research Foundation (2020B1515120017), and the Academic Frontier Youth Team Project to Xiaochuan Wang from Huazhong University of Science and Technology.

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  1. Longfei Li and Yanli Jiang contributed equally to this paper.

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, 430030, China

    Longfei Li, Yanli Jiang, Gang Wu, Yacoubou Abdoul Razak Mahaman, Dan Ke, Qun Wang, Bin Zhang, Jian-Zhi Wang, Hong-Lian Li, Rong Liu & Xiaochuan Wang

  2. Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, JS, China

    Jian-Zhi Wang & Xiaochuan Wang

  3. Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, 430056, China

    Jian-Zhi Wang & Xiaochuan Wang

  4. Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China

    Xiaochuan Wang

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  1. Longfei Li
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Contributions

Xiaochuan Wang designed all experiments and organized all results, including the writing of the manuscript. Longfei Li and Yanli Jiang planned and performed all experiments and participated in the writing of the manuscript. Gang Wu, Yacoubou Abdoul Razak Mahaman, Dan Ke, and Qun Wang assisted with the manuscript preparation. Bin Zhang and Hong-Lian Li analyzed the data. Jian-Zhi Wang and Rong Liu analyzed and interpreted the data.

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Correspondence to Rong Liu or Xiaochuan Wang.

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Li, L., Jiang, Y., Wu, G. et al. Phosphorylation of Truncated Tau Promotes Abnormal Native Tau Pathology and Neurodegeneration. Mol Neurobiol 59, 6183–6199 (2022). https://doi.org/10.1007/s12035-022-02972-7

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