The proNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau
Date
2018
Authors
Shen, L.L.
Mañucat-Tan, N.B.
Gao, S.H.
Li, W.W.
Zeng, F.
Zhu, C.
Wang, J.
Bu, X.L.
Liu, Y.H.
Gao, C.Y.
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Advisors
Journal Title
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Type:
Journal article
Citation
Molecular Psychiatry, 2018; 23(8):1813-1824
Statement of Responsibility
Lin-Lin Shen, Noralyn B. Mañucat-Tan, Shi-Hao Gao, Wei-Wei Li, Fan Zeng, Chi Zhu, Jun Wang, Xian-Le Bu, Yu-Hui Liu, Chang-Yue Gao, Zhi-Qiang Xu, Larisa Bobrovskaya, Peng Lei, Jin-Tai Yu, Weihong Song, Hua-Dong Zhou, Xiu-Qing Yao, Xin-Fu Zhou, Yan-Jiang Wang
Conference Name
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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Data source: Electronic supplementary material, https://doi.org/10.1038/s41380-018-0071-z
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© Macmillan Publishers Limited, part of Springer Nature 2018