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.2021-09-242021-09-242018Molecular Psychiatry, 2018; 23(8):1813-18241359-41841476-5578https://hdl.handle.net/2440/132283Data source: Electronic supplementary material, https://doi.org/10.1038/s41380-018-0071-zTau 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.en© Macmillan Publishers Limited, part of Springer Nature 2018FTLD-tauBrainNeuronsCells, CulturedAnimalsMice, TransgenicMemory DisordersNerve Growth Factortau ProteinsReceptors, Nerve Growth FactorProtein PrecursorsSignal TransductionPhosphorylationFemaleMaleProto-Oncogene Proteins c-aktFrontotemporal Lobar DegenerationPrimary Cell CultureGlycogen Synthase Kinase 3 betaJournal article10.1038/s41380-018-0071-z2021-09-242-s2.0-85047999140562681Zhou, X.F. [0000-0002-8687-0175]