Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups

Yoshiyuki Soeda, Misato Yoshikawa, Osborne F X Almeida, Akio Sumioka, Sumihiro Maeda, Hiroyuki Osada, Yasumitsu Kondoh, Akiko Saito, Tomohiro Miyasaka, Tetsuya Kimura, Masaaki Suzuki, Hiroko Koyama, Yuji Yoshiike, Hachiro Sugimoto, Yasuo Ihara, Akihiko Takashima

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Abstract

Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimers disease; the neurofibrillary tangle load correlates strongly with clinical progression of the disease. A growing body of evidence indicates that tau oligomer formation precedes the appearance of neurofibrillary tangles and contributes to neuronal loss. Here we show that tau oligomer formation can be inhibited by compounds whose chemical backbone includes 1,2-dihydroxybenzene. Specifically, we demonstrate that 1,2-dihydroxybenzene-containing compounds bind to and cap cysteine residues of tau and prevent its aggregation by hindering interactions between tau molecules. Further, we show that orally administered DL-isoproterenol, an adrenergic receptor agonist whose skeleton includes 1,2-dihydroxybenzene and which penetrates the brain, reduces the levels of detergent-insoluble tau, neuronal loss and reverses neurofibrillary tangle-associated brain dysfunction. Thus, compounds that target the cysteine residues of tau may prove useful in halting the progression of Alzheimers disease and other tauopathies.

Original languageEnglish
Article number10216
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015 Dec 16
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

Soeda, Y., Yoshikawa, M., Almeida, O. F. X., Sumioka, A., Maeda, S., Osada, H., Kondoh, Y., Saito, A., Miyasaka, T., Kimura, T., Suzuki, M., Koyama, H., Yoshiike, Y., Sugimoto, H., Ihara, Y., & Takashima, A. (2015). Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups. Nature Communications, 6, [10216]. https://doi.org/10.1038/ncomms10216