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

Polymerization of monomeric amyloid-beta peptides (A beta) 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 A beta peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigate the effects of mono- and biflavonoids in A beta 42-induced toxicity and fibrillogenesis and find that the biflavonoid taiwaniaflavone (TF) effectively and specifically inhibits A beta 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 A beta fibrillogenesis correlate with their varying cytoprotective efficacies. We also find that other biflavonoids, namely, 2',8 ''-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit A beta toxicity and fibrillogenesis, implying that the participation of two monoflavonoids in a single biflavonoid molecule enhances their activity. Biflavonoids, while strongly inhibiting A beta fibrillogenesis, accumulate nontoxic A beta oligomeric structures, suggesting that these are off-pathway oligomers. Moreover, TF abrogates the toxicity of preformed A beta oligomers and fibrils, indicating that TF and other biflavonoids may also reduce the toxicity of toxic A beta species. Altogether, our data clearly show that biflavonoids, possibly because of the possession of two A beta binders separated by an appropriate size linker, are likely to be promising therapeutics for suppressing A beta toxicity.