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.

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

“…Recent studies have been devoted toward the design of antibodies (Hillen et al, 2010), peptides (Esteras-Chopo et al, 2008), flavonoids (Thapa et al, 2011), or other pharmaceutical compounds ) to block A␤ peptide oligomerization, but the in vivo efficiency of such a strategy requires extensive knowledge of the oligomerization process and the toxicity of the various oligomeric forms. Other studies have focused on the functional interactions between A␤ peptide and glutamate receptors (Decker et al, 2010b;Hu et al, 2009;Texidó et al, 2011;Zhao et al, 2010) or have attempted to reinforce neuronal defenses through the neurotrophic effects of growth factors or membrane lipids such as docosahexaenoic acid (Ma et al, 2009).…”

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

“…3.2). Thus, the biflavonoid was found to be more effective at reducing A" fibril extension compared to the monoflavonoid (Thapa et al 2011). …”

“…The polyphenol that contains both ferulic acid and styryl benzene has been shown to be more effective than either of the two individual compounds . It has been further suggested that the dimers of A" binding monoflavonoids, separated by an appropriate size linker, may serve as a general structure for inhibitors of A" aggregation and toxicity (Thapa et al 2011). Such biflavonoid compounds may be promising therapeutic candidates for AD.…”

“…A study that compared the effects of the monoflavonoid apigenin Fig. 3.2 The initial rate of A"42 fiber extension in the presence or absence of biflavonoid taiwaniaflavone (•, BF) or monoflavonoid apigenin (ı, AP) obtained by extrapolating Thioflavin-T florescence data (Reprinted with permission from Thapa et al 2011) and biflavonoid taiwaniaflavone on A" fibril formation showed that the biflavonoid reduced the final level of Thioflavin-T fluorescence to a greater extent compared to the monoflavonoid (Thapa et al 2011). The study also showed that neither the monoflavonoids nor the biflavonoids significantly affected the nucleation step.…”

Proceedings of conference on Mechanism-Based Development of Natural Products for Human Health

“…Using small molecules to prevent the aggregation of Aβ is an effective therapeutic strategy for AD. Monoflavonoids and biflavonoids were reported as Aβ aggregation inhibitors and cyto-protectors 2 . But the mechanism of action remains unknown.…”