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Friend or foe: role of pathological tau in neuronal death

Molecular Psychiatry volume 28, pages 2215–2227 (2023)Cite this article

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Abstract

Neuronal death is one of the most common pathological hallmarks of diverse neurological diseases, which manifest varying degrees of cognitive or motor dysfunction. Neuronal death can be classified into multiple forms with complicated and unique regulatory signaling pathways. Tau is a key microtubule-associated protein that is predominantly expressed in neurons to stabilize microtubules under physiological conditions. In contrast, pathological tau always detaches from microtubules and is implicated in a series of neurological disorders that are characterized by irreversible neuronal death, such as necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-dependent neuronal death and phagocytosis by microglia. However, recent studies have also revealed that pathological tau can facilitate neuron escape from acute apoptosis, delay necroptosis through its action on granulovacuolar degeneration bodies (GVBs), and facilitate iron export from neurons to block ferroptosis. In this review, we briefly describe the current understanding of how pathological tau exerts dual effects on neuronal death by acting as a double-edged sword in different neurological diseases. We propose that elucidating the mechanism by which pathological tau affects neuronal death is critical for exploring novel and precise therapeutic strategies for neurological disorders.

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Fig. 1: The dual roles of pathological tau in neuronal apoptosis.
Fig. 2: Pathological tau induces necroptosis on the one hand and may delay necroptosis through GVBs on the other hand.
Fig. 3: Pathological tau induces ferroptosis, and soluble tau exerts neuroprotective effects by reducing iron overload.
Fig. 4: Pathological tau induces pyroptosis.
Fig. 5: Pathological tau induces neuron phagocytosis by microglia.

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Funding

This study was partially supported by the National Key Research and Development Program of China (2019YFE0121200 to LQZ), the National Natural Science Foundation of China (82030032 to LQZ, 82261138555, 32070960 to DL, 82260209 and 81960221 to XPY, and 82260454 to BB), Top-Notch Young Talents Program of China of 2014 and Academic Frontier Youth Team of Huazhong University of Science and Technology (to LQZ); the Hubei Provincial Natural Science Foundation (2022CFA004 to LQ); the National Science & Technology Fundamental Resource Investigation Program of China (2018FY100903 to XPY); and Science and Technology Project Founded by the Education Department of Jiangxi Province (GJJ201834 to MXW). Jiangxi Provincial Health Commission Science and Technology Plan Project (202212021 to MXW and 202311506 to ZYC), and Jiangxi Provincial Administration of Traditional Chinese Medicine Science and Technology Plan Project (2022A322 to ZYC).

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  1. These authors contributed equally: Moxin Wu, Zhiying Chen, Min Jiang.

Authors and Affiliations

  1. Department of Medical Laboratory, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China

    Moxin Wu

  2. Jiujiang Clinical Precision Medicine Research Center, Jiujiang, 332000, China

    Moxin Wu, Zhiying Chen, Min Jiang, Bing Bao, Dongling Li & Xiaoping Yin

  3. Department of Neurology, Affiliated Hospital of Jiujiang University, Jiujiang, 332000, China

    Zhiying Chen, Bing Bao, Dongling Li & Xiaoping Yin

  4. Department of Anesthesiology, Shanxi Bethune Hospital, Taiyuan, 030032, China

    Xueren Wang

  5. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xueren Wang

  6. Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Dan Liu

  7. Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ling-Qiang Zhu

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The initial idea for this review was generated by LQZ and, DL, and the manuscript was written and revised by MXW, ZYC and MJ. In addition, MXW, MJ and BB contributed to illustration preparation; LQZ, XPY, DLL and ZYC edited the manuscript; DL, XRW, XPY and MXW read, reviewed, and approved the final manuscript. The final version of the manuscript was approved by all authors.

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Wu, M., Chen, Z., Jiang, M. et al. Friend or foe: role of pathological tau in neuronal death. Mol Psychiatry 28, 2215–2227 (2023). https://doi.org/10.1038/s41380-023-02024-z

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