PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo

PLoS One. 2015 Feb 6;10(2):e0117511. doi: 10.1371/journal.pone.0117511. eCollection 2015.

Abstract

In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Mutation, Missense
  • Protein Aggregation, Pathological / drug therapy*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Tauopathies / drug therapy*
  • Tauopathies / genetics
  • Tauopathies / metabolism
  • Tauopathies / pathology
  • tau Proteins / antagonists & inhibitors*
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • 3-(2-(1H-indol-6-yl)ethenyl)-5-(2-(2-methoxy-4-(2-pyridylmethoxy)phenyl)ethenyl)-1H-pyrazole
  • Heterocyclic Compounds, 4 or More Rings
  • Indoles
  • MAPT protein, human
  • Pyrazoles
  • tau Proteins

Grants and funding

The authors received no specific funding for this work. Pharma Eight Co., Ltd., ChemGenesis Inc. and Eisai Co., Ltd. provided support in the form of salaries for authors M Okuda, YF, SN, YS, YN, HS, IH, M. Ogo, SA and YI but did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.