title: Inhibition of tau aggregation by a rosamine derivative that blocks tau intermolecular disulfide cross-linking.
abstract: Abnormal tau aggregates are presumed to be neurotoxic and are an important therapeutic target for multiple neurodegenerative disorders including Alzheimer's disease. Growing evidence has shown that tau intermolecular disulfide cross-linking is critical in generating tau oligomers that serve as a building block for higher-order aggregates. Here we report that a small molecule inhibitor prevents tau aggregation by blocking the generation of disulfide cross-linked tau oligomers. Among the compounds tested, a rosamine derivative bearing mild thiol reactivity selectively labeled tau and effectively inhibited oligomerization and fibrillization processes in vitro. Our data suggest that controlling tau oxidation status could be a new therapeutic strategy for prevention of abnormal tau aggregation.
authors.affiliation: Center for Neuro-medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST) , Seoul , Republic of Korea .
authors.forename: Md Mamunul
authors.initials: MM
authors.lastname: Haque
authors.forename: Dohee
authors.initials: D
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yu
authors.forename: Sungsu
authors.initials: S
authors.lastname: Lim
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Kim
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Chang
authors.forename: Hyung-Ho
authors.initials: HH
authors.lastname: Ha
authors.forename: Yun Kyung
authors.initials: YK
authors.lastname: Kim
mesh_terms: D052160:Benzothiazoles; D004220:Disulfides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D055808:Drug Discovery; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005456:Fluorescent Dyes / Q000737:chemistry*; D015870:Gene Expression; D006801:Humans; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D066329:Protein Aggregates; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry*; D012996:Solutions; D013050:Spectrometry, Fluorescence; D013844:Thiazoles; D014966:Xanthenes / Q000737:chemistry*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D052160:Benzothiazoles; D004220:Disulfides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D066329:Protein Aggregates; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D012996:Solutions; D013844:Thiazoles; D014966:Xanthenes; D016875:tau Proteins; C009462:thioflavin T
keywords: In-gel fluorescence; Tau oligomerization; intermolecular disulfide bond; rosamine; small molecule inhibitor; thiol reactivity