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https://hdl.handle.net/2440/132283
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Type: | Journal article |
Title: | The proNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau |
Author: | 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. Xu, Z.Q. Bobrovskaya, L. Lei, P. Yu, J.T. Song, W. Zhou, H.D. Yao, X.Q. Zhou, X.F. Wang, Y.J. |
Citation: | Molecular Psychiatry, 2018; 23(8):1813-1824 |
Publisher: | Springer Nature |
Issue Date: | 2018 |
ISSN: | 1359-4184 1476-5578 |
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 |
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. |
Keywords: | FTLD-tau |
Rights: | © Macmillan Publishers Limited, part of Springer Nature 2018 |
DOI: | 10.1038/s41380-018-0071-z |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1021409 http://purl.org/au-research/grants/nhmrc/1020567 |
Published version: | http://dx.doi.org/10.1038/s41380-018-0071-z |
Appears in Collections: | Medicine publications |
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