The proNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau

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dc.contributor.authorShen, L.L.
dc.contributor.authorMañucat-Tan, N.B.
dc.contributor.authorGao, S.H.
dc.contributor.authorLi, W.W.
dc.contributor.authorZeng, F.
dc.contributor.authorZhu, C.
dc.contributor.authorWang, J.
dc.contributor.authorBu, X.L.
dc.contributor.authorLiu, Y.H.
dc.contributor.authorGao, C.Y.
dc.contributor.authorXu, Z.Q.
dc.contributor.authorBobrovskaya, L.
dc.contributor.authorLei, P.
dc.contributor.authorYu, J.T.
dc.contributor.authorSong, W.
dc.contributor.authorZhou, H.D.
dc.contributor.authorYao, X.Q.
dc.contributor.authorZhou, X.F.
dc.contributor.authorWang, Y.J.
dc.date.issued2018
dc.descriptionData source: Electronic supplementary material, https://doi.org/10.1038/s41380-018-0071-z
dc.description.abstractTau 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.
dc.description.statementofresponsibilityLin-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
dc.identifier.citationMolecular Psychiatry, 2018; 23(8):1813-1824
dc.identifier.doi10.1038/s41380-018-0071-z
dc.identifier.issn1359-4184
dc.identifier.issn1476-5578
dc.identifier.orcidZhou, X.F. [0000-0002-8687-0175]
dc.identifier.urihttps://hdl.handle.net/2440/132283
dc.language.isoen
dc.publisherSpringer Nature
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1021409
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1020567
dc.rights© Macmillan Publishers Limited, part of Springer Nature 2018
dc.source.urihttps://doi.org/10.1038/s41380-018-0071-z
dc.subjectFTLD-tau
dc.subject.meshBrain
dc.subject.meshNeurons
dc.subject.meshCells, Cultured
dc.subject.meshAnimals
dc.subject.meshMice, Transgenic
dc.subject.meshMemory Disorders
dc.subject.meshNerve Growth Factor
dc.subject.meshtau Proteins
dc.subject.meshReceptors, Nerve Growth Factor
dc.subject.meshProtein Precursors
dc.subject.meshSignal Transduction
dc.subject.meshPhosphorylation
dc.subject.meshFemale
dc.subject.meshMale
dc.subject.meshProto-Oncogene Proteins c-akt
dc.subject.meshFrontotemporal Lobar Degeneration
dc.subject.meshPrimary Cell Culture
dc.subject.meshGlycogen Synthase Kinase 3 beta
dc.titleThe proNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau
dc.typeJournal article
pubs.publication-statusPublished

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