Biflavonoids Are Superior to Monoflavonoids in Inhibiting Amyloid-β Toxicity and Fibrillogenesis via Accumulation of Nontoxic Oligomer-like Structures

摘要

Polymerization of monomeric amyloid-β peptides (Aβ) into soluble oligomers and insoluble fibrils is one of the major pathwaysntriggering the pathogenesis of Alzheimer’s disease (AD). Using small molecules to prevent the polymerization of Aβ peptides can,ntherefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in Aβ42-ninduced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits Aβ toxicitynand fibrillogenesis. Compared to TF, the monoflavonoid apigenin (AP) is less effective and less specific. Our data show thatndifferential effects of the mono- and biflavonoids in Aβ fibrillogenesis correlate with their varying cytoprotective efficacies.We alsonfind that other biflavonoids, namely, 20n,800n-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit Aβ toxicity andnfibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity.nBiflavonoids, while strongly inhibiting Aβ fibrillogenesis, accumulate nontoxic Aβ oligomeric structures, suggesting that these arenoff-pathway oligomers. Moreover, TF abrogates the toxicity of preformed Aβ oligomers and fibrils, indicating that TF and othernbiflavonoids may also reduce the toxicity of toxic Aβ species. Altogether, our data clearly show that biflavonoids, possibly because ofnthe possession of two Aβ binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing Aβntoxicity.