title: Biflavonoids are superior to monoflavonoids in inhibiting amyloid-β toxicity and fibrillogenesis via accumulation of nontoxic oligomer-like structures.
abstract: Polymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of Aβ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Aβ42-induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Aβ toxicity and fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show that differential effects of the mono- and biflavonoids in Aβ fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting Aβ fibrillogenesis, accumulate nontoxic Aβ oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Aβ oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two Aβ binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Aβ toxicity.
authors.affiliation: Department of Biomaterials Engineering, Chosun University, Gwanju 501-759, Republic of Korea.
authors.forename: Arjun
authors.initials: A
authors.lastname: Thapa
authors.forename: Eun-Rhan
authors.initials: ER
authors.lastname: Woo
authors.forename: Eva Y
authors.initials: EY
authors.lastname: Chi
authors.forename: Md Golam
authors.initials: MG
authors.lastname: Sharoar
authors.forename: Hong-Guang
authors.initials: HG
authors.lastname: Jin
authors.forename: Song Yub
authors.initials: SY
authors.lastname: Shin
authors.forename: Il-Seon
authors.initials: IS
authors.lastname: Park
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D047310:Apigenin / Q000378:metabolism; D052160:Benzothiazoles; D044946:Biflavonoids / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002942:Circular Dichroism; D047309:Flavones / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D010636:Phenols / Q000378:metabolism; D059808:Polyphenols; D012995:Solubility; D013844:Thiazoles / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D044946:Biflavonoids; D047309:Flavones; D005419:Flavonoids; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D010636:Phenols; D059808:Polyphenols; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C518734:taiwaniaflavone; C009462:thioflavin T; D047310:Apigenin; D020169:Caspases