title: Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups.
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.
authors.affiliation: Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Soeda
authors.affiliation: Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Department of Stress Neurology and Neurogenesis, Max Planck Institute of Psychiatry, Kraepelinstrasse, 2-10, Munich 80804, Germany.
authors.forename: Osborne F X
authors.initials: OF
authors.lastname: Almeida
authors.affiliation: Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Sumioka
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158-2261, USA.
authors.forename: Sumihiro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), RIKEN, Wako, Saitama 351-0198, Japan.|Antibiotics Laboratory, Advanced Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.affiliation: Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science (CSRS), RIKEN, Wako, Saitama 351-0198, Japan.|Antibiotics Laboratory, Advanced Science Institute, RIKEN, Wako, Saitama 351-0198, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Kondoh
authors.affiliation: Graduate School of Engineering, Osaka Electro-communication University (OECU), 18-8 Hatsu-cho, Osaka 572-8530, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Miyasaka
authors.affiliation: Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Division of Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Alzheimer's Disease Project Team, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yoshiike
authors.affiliation: Laboratory of Structural Neuropathology, Graduate School of Brain Science, Doshisha University, Kizugawa, Kyoto 619-0225, Japan.
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.|Laboratory of Cognition and Aging, Doshisha University, Kizugawa 619-0225, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ihara
authors.affiliation: Department of Aging Neurobiology, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
mesh_terms: D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002396:Catechols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D007545:Isoproterenol / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D058105:Polymerization; D016875:tau Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D002396:Catechols; D016875:tau Proteins; D003545:Cysteine; D007545:Isoproterenol; C034221:catechol