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

Linlin Shen, Noralyn Basco Mañucat-Tan, Shihao Gao, Weiwei Li, Fan Zeng, Chi Zhu, Jun Wang, Xian Le Bu, Yuhui Liu, Changyue Yue Gao, Zhiqiang Xu, Larisa Bobrovskaya, Peng Lei, Jintai Yu, Weihong Song, Huadong Zhou, Xiuqing Yao, X. F. Zhou, Yanjiang Wang

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1813-1824
Number of pages12
JournalMolecular Psychiatry
Volume23
Issue number8
DOIs
Publication statusPublished - Aug 2018
Externally publishedYes

Keywords

  • Tau pathology
  • ProNGF/p75NT pathway
  • therapeutic targets
  • frontotemporal lobar degeneration
  • neurotrophin receptor (p75 NTR)
  • tauopathy

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