TY - JOUR
T1 - The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau
AU - Shen, Linlin
AU - Mañucat-Tan, Noralyn Basco
AU - Gao, Shihao
AU - Li, Weiwei
AU - Zeng, Fan
AU - Zhu, Chi
AU - Wang, Jun
AU - Bu, Xian Le
AU - Liu, Yuhui
AU - Gao, Changyue Yue
AU - Xu, Zhiqiang
AU - Bobrovskaya, Larisa
AU - Lei, Peng
AU - Yu, Jintai
AU - Song, Weihong
AU - Zhou, Huadong
AU - Yao, Xiuqing
AU - Zhou, X. F.
AU - Wang, Yanjiang
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - Tau pathology
KW - ProNGF/p75NT pathway
KW - therapeutic targets
KW - frontotemporal lobar degeneration
KW - neurotrophin receptor (p75 NTR)
KW - tauopathy
UR - http://www.scopus.com/inward/record.url?scp=85047999140&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1021409
UR - http://purl.org/au-research/grants/NHMRC/1020567
U2 - 10.1038/s41380-018-0071-z
DO - 10.1038/s41380-018-0071-z
M3 - Article
SN - 1476-5578
VL - 23
SP - 1813
EP - 1824
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 8
ER -
