Research Paper Volume 11, Issue 17 pp 6762—6791

Knockout of p75 neurotrophin receptor attenuates the hyperphosphorylation of Tau in pR5 mouse model

Noralyn B. Mañucat-Tan 1, *, , Lin-Lin Shen 2, *, , Larisa Bobrovskaya 1, , Mohammed Al-hawwas 1, , Fiona H. Zhou 1, , Yan-Jiang Wang 2, , Xin-Fu Zhou 1, ,

  • 1 School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide 5000, Australia
  • 2 Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing 400042, China
* Equal contribution

received: January 26, 2019 ; accepted: August 12, 2019 ; published: September 3, 2019 ;
How to Cite

Copyright © 2019 Mañucat-Tan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


p75 neurotrophin receptor (p75NTR) has been implicated in Alzheimer’s disease (AD). However, whether p75NTR is involved in Tau hyperphosphorylation, one of the pathologies observed in AD, remains unclear. In our previous study, the extracellular domain of p75NTR blocked amyloid beta (Aβ) toxicity and attenuated Aβ-induced Tau hyperphosphorylation. Here we show that, in the absence of Aβ, p75NTR regulates Tau phosphorylation in the transgenic mice with the P301L human Tau mutation (pR5). The knockout of p75NTR in pR5 mice attenuated the phosphorylation of human Tau. In addition, the elevated activity of kinases responsible for Tau phosphorylation including glycogen synthase kinase 3 beta; cyclin-dependent-kinase 5; and Rho-associated protein kinase was also inhibited when p75NTR is knocked out in pR5 mice at 9 months of age. The increased caspase-3 activity observed in pR5 mice was also abolished in the absence of p75NTR. Our study also showed that p75NTR is required for Aβ- and pro-brain derived neurotrophin factor (proBDNF)-induced Tau phosphorylation, in vitro. Overall, our data indicate that p75NTR is required for Tau phosphorylation, a key event in the formation of neurofibrillary tangles, another hallmark of AD. Thus, targeting p75NTR could reduce or prevent the pathologic hyperphosphorylation of Tau.


p75NTR: p75 neurotrophin receptor; AD: Alzheimer’s disese; Aβ: amyloid beta; p75KO: p75NTR ExonIII-/- mice; pR75KO: PR5/ p75NTR ExonIII-/- mice; Wt: wild type mice; AT8: Ser202/Thr205; p75ECD-Fc: p75NTR fused to human Fc region; NFTs: neurofibrillary tangles; GSK3β: glycogen synthase 3 beta; AMP: cyclic adenosine monophosphate; PKA: dependent protein kinase A; Cdk5: cyclin-dependent protein kinase 5; ROCK: rho-kinase; JNK: c-Jun N-terminal kinase; PI3K: phosphatidylinositol kinase-3; NGF: nerve growth factor; proBDNF: pro-brain derived neurotrophic factor; pR5: P301L mutation with Parkinsonism linked with chromosome 17.