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 and Akihiko Takashima ()
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Yoshiyuki Soeda: National Center for Geriatrics and Gerontology
Misato Yoshikawa: National Center for Geriatrics and Gerontology
Osborne F. X. Almeida: Max Planck Institute of Psychiatry, Kraepelinstrasse, 2-10, Munich 80804, Germany
Akio Sumioka: National Center for Geriatrics and Gerontology
Sumihiro Maeda: Gladstone Institute of Neurological Disease, University of California
Hiroyuki Osada: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), RIKEN
Yasumitsu Kondoh: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), RIKEN
Akiko Saito: Graduate School of Engineering, Osaka Electro-communication University (OECU)
Tomohiro Miyasaka: Faculty of Life and Medical Sciences, Doshisha University
Tetsuya Kimura: National Center for Geriatrics and Gerontology
Masaaki Suzuki: Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology
Hiroko Koyama: Gifu University Graduate School of Medicine
Yuji Yoshiike: Alzheimer's Disease Project Team, National Center for Geriatrics and Gerontology
Hachiro Sugimoto: Laboratory of Structural Neuropathology, Graduate School of Brain Science, Doshisha University
Yasuo Ihara: Faculty of Life and Medical Sciences, Doshisha University
Akihiko Takashima: National Center for Geriatrics and Gerontology

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract Neurofibrillary tangles, composed of hyperphosphorylated tau fibrils, are a pathological hallmark of Alzheimer’s 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 Alzheimer’s disease and other tauopathies.

Date: 2015
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DOI: 10.1038/ncomms10216

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