Hepta-Histidine Inhibits Tau Aggregation

  • ACS Chem Neurosci. 2021 Aug 18;12(16):3015-3027. doi: 10.1021/acschemneuro.1c00164.
Kanoh Kondo  1 ,  Teikichi Ikura  2 ,  Hikari Tanaka  1 ,  Kyota Fujita  1 ,  Sumire Takayama  1 ,  Yuki Yoshioka  1 ,  Kazuhiko Tagawa  1 ,  Hidenori Homma  1 ,  Su Liu  3 ,  Ryosuke Kawasaki  3 ,  Yong Huang  1 ,  Nobutoshi Ito  2 ,  Shin-Ichi Tate  3 ,  Hitoshi Okazawa  1
Affiliations
  • 1. Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  • 2. Department of Structural Biology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510 Tokyo, Japan.
  • 3. Department of Mathematical and Life Sciences, Graduate School for Integrated Sciences for Life, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
PMID: 34319089 DOI: 10.1021/acschemneuro.1c00164
Abstract

Tau aggregation is a central hallmark of tauopathies such as frontotemporal lobar degeneration and progressive supranuclear palsy as well as of Alzheimer's disease, and it has been a target for therapeutic development. Herein, we unexpectedly found that hepta-histidine (7H), an inhibitor of the interaction between Ku70 and Huntingtin proteins, suppresses aggregation of Tau-R3 peptides in vitro. Addition of the trans-activator of transcription (TAT) sequence (YGRKKRRQRRR) derived from the TAT protein to 7H increased its permeability into cells, and TAT-7H treatment of iPS cell-derived neurons carrying Tau or APP mutations suppressed Tau phosphorylation. These results indicate that 7H is a promising lead compound for developing anti-aggregation drugs against Tau-related neurodegenerative diseases including Alzheimer's disease (AD).

Keywords
Hepta-histidine; TAT; aggregation; neurodegenerative diseases; tau.
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