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

研究成果: Article査読

77 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号10216
ジャーナルNature communications
6
DOI
出版ステータスPublished - 2015 12月 16
外部発表はい

ASJC Scopus subject areas

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 一般
  • 物理学および天文学(全般)

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