title: C-Glycosylflavones Alleviate Tau Phosphorylation and Amyloid Neurotoxicity through GSK3β Inhibition.
abstract: Alzheimer's disease (AD) is the most common brain disorder worldwide. Aberrant tau hyperphosphorylation and accumulation play critical roles in the formation of neurofibrillary tangles highly associated with neuronal dysfunction and cognitive impairment in AD pathogenesis. Glycogen synthase kinase-3β (GSK3β) is a key kinase responsible for tau hyperphosphorylation. Selective inhibition of GSK3β is a promising strategy in AD therapy. Corn silks (CS, Zea mays L.) have been traditionally used as a medicinal herb and recently noted for their potentially cognitive benefits. However, the neuroprotective components of CS and their molecular mechanism have received little attention to date. As part of our effort screening phytochemicals against a broad panel of kinases targeting AD tauopathy, we found inhibition of GSK3β by CS extracts. Subsequent bioassay-guided fractionation led to the isolation and identification of two 6-C-glycosylflavones, isoorientin (1) and 3'-methoxymaysin (2), with selective inhibition against GSK3β in vitro. Enzyme kinetics and molecular docking studies demonstrated that 1 specifically inhibited GSK3β via an ATP noncompetitive mechanism, acting as a substrate competitive inhibitor of GSK3β. Further in vitro cellular studies demonstrated that 1 effectively attenuated tau phosphorylation mediated by GSK3β and was neuroprotective against β-amyloid-induced tau hyperphosphorylation and neurotoxicity in SH-SY5Y cells. The C-glycosylflavones represent new lead candidates with a novel mechanism of action for the development of AD phytopharmaceuticals.
authors.affiliation: Department of Molecular Biosciences and Bioengineering, and ‡Department of Chemistry, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Molecular Biosciences and Bioengineering, and ‡Department of Chemistry, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Molecular Biosciences and Bioengineering, and ‡Department of Chemistry, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Wei Wen
authors.initials: WW
authors.lastname: Su
authors.affiliation: Department of Molecular Biosciences and Bioengineering, and ‡Department of Chemistry, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Williams
authors.affiliation: Department of Molecular Biosciences and Bioengineering, and ‡Department of Chemistry, University of Hawaii at Manoa , Honolulu, Hawaii 96822, United States.
authors.forename: Qing X
authors.initials: QX
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology; D047311:Luteolin / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
chemical_list: C517305:3'-methoxypuerarin; D016229:Amyloid beta-Peptides; C421808:C-glucosylflavone; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007529:Isoflavones; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D000255:Adenosine Triphosphate; C057912:homoorientin; D038362:Glycogen Synthase Kinase 3; D019311:Staurosporine; D047311:Luteolin
keywords: Alzheimers; C-Glycosylflavone; GSK3; amyloid; neuroprotection; tau phosphorylation