The FK506-binding protein FKBP52 in vitro induces aggregation of truncated Tau forms with prion-like behavior

FASEB J. 2015 Aug;29(8):3171-81. doi: 10.1096/fj.14-268243. Epub 2015 Apr 17.


Tauopathies, including Alzheimer's disease (AD), are neurodegenerative diseases associated with the pathologic aggregation of human brain Tau protein. Neuronal Tau is involved in microtubule (MT) formation and stabilization. We showed previously that the immunophilin FK506-binding protein of MW ∼52 kDa (FKBP52) interferes with this function of full-length Tau and provokes aggregation of a disease-related mutant of Tau. To dissect the molecular interaction between recombinant human FKBP52 and Tau, here, we study the effect of FKBP52 on a functional Tau fragment (Tau-F4, Ser(208)-Ser(324)) containing part of the proline- rich region and MT-binding repeats. Therefore, we perform MT assembly and light-scattering assays, blue native PAGE analysis, electron microscopy, and Tau seeding experiments in SH-SY5Y human neuroblastoma cells. We show that FKBP52 (6 µM) prevents MT formation generated by Tau-F4 (5 µM) and induces Tau-F4 oligomerization and aggregation. Electron microscopy analyses show granular oligomers and filaments of Tau-F4 after short-time FKBP52 incubation. We demonstrate that the terminal parts of Tau interfere with the effects of FKBP52. Finally, we find that FKBP52-induced Tau-F4 oligomers cannot only generate in vitro, direct conformational changes in full-length Tau and that their uptake into neuronal cells can equally lead to aggregation of wild-type endogenous Tau. This suggests a potential prion-like property of these particular Tau-F4 aggregates. Collectively, our results strengthen the hypothesis of FKBP52 involvement in the Tau pathogenicity process.

Keywords: Tau assembly; immunophilin; microtubule; seeding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Brain / metabolism
  • Cell Line, Tumor
  • Humans
  • Male
  • Microtubules / metabolism
  • Prions / metabolism*
  • Protein Binding / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Tacrolimus Binding Proteins / metabolism*
  • Tauopathies / metabolism
  • tau Proteins / metabolism*


  • Prions
  • tau Proteins
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 4