Abstract

Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 81625007, 91749206 and 81571239), National Health and Medical Research Council (APP1021409 to X-FZ and Y-JW and APP1020567 fellowship grant to X-FZ). NBM-T was supported by UniSA President Scholarship and Overseas Student Scholarship. We wish to thank Professor Juergen Gotz from Queensland Brain Institute, Queensland University (Australia) for sharing the P301L transgenic mice with us. We also thank Professors  Jianzhi Wang and Rong Liu at Huazhong University of Science and Technology (China) for pEGFP-tau2N4R plasmid.

Author contributions

Y-JW, X-FZ and X-QY conceived and designed the project, L-LS, NBM-T, S-HG, CZ, JW, FZ, X-LB, Y-HL, C-YG and Z-QX performed animal and in vitro experiments, W-WL and L-LS performed human sample experiments, LB, WS, H-DZ, J-TY, PL, X-QY, X-FZ and Y-JW analyzed data. L-LS, X-FZ and Y-JW wrote the manuscript.

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Author notes

  1. These authors contributed equally: Lin-Lin Shen, Noralyn B. Mañucat-Tan.

Affiliations

  1. Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China

    • Lin-Lin Shen
    • , Wei-Wei Li
    • , Fan Zeng
    • , Chi Zhu
    • , Jun Wang
    • , Xian-Le Bu
    • , Yu-Hui Liu
    • , Chang-Yue Gao
    • , Zhi-Qiang Xu
    • , Hua-Dong Zhou
    • , Xiu-Qing Yao
    •  & Yan-Jiang Wang
  2. School of Pharmacy and Medical Sciences and Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia

    • Noralyn B. Mañucat-Tan
    • , Larisa Bobrovskaya
    •  & Xin-Fu Zhou
  3. Department of Neurobiology, College of Basic Medical Science, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, 400038, Chongqing, China

    • Shi-Hao Gao
  4. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, China

    • Peng Lei
  5. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

    • Jin-Tai Yu
  6. Townsend Family Laboratories, Department of Psychiatry, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada

    • Weihong Song
  7. State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China

    • Yan-Jiang Wang

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Correspondence to Xiu-Qing Yao or Xin-Fu Zhou or Yan-Jiang Wang.

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https://doi.org/10.1038/s41380-018-0071-z

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