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

Department of Biomaterials Engineering, Chosun University, Gwanju 501-759, Republic of Korea.
Biochemistry (Impact Factor: 3.01). 02/2011; 50(13):2445-55. DOI: 10.1021/bi101731d
Source: PubMed

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.

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    • "Besides monomeric flavonoids, Selaginella is a rich source for biflavonoids (Setyawan, 2011). Medicinally, biflavonoids associate with assorted pharmacological properties including antimicrobial, antiviral, anticancer, anti-inflammatory, and anti-fibrillogenesis activities (Ma et al., 2001; Tang et al., 2003; Pan et al., 2005; Setyawan, 2011; Thapa et al., 2011). "
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    • "This result is similar to that reported using heme to prevent amyloid formation of the double mutant form of sperm whale apomyoglobin (Iannuzzi et al., 2007). The " remodeling " ability of some ligands that results into formation of non-toxic unstructured aggregates instead of the toxic species formed during the amyloidogenic process, has recently been reported for resveratrol (Ladiwala et al., 2010), biflavonoids (Thapa et al., 2011) and rifamycin (Woods et al., 2011). More generally, depending on their structures, aromatic small molecules are believed to act on the amyloidogenic process through different mechanisms, resulting in formation of various non-fibrillar structures (Ladiwala et al., 2011). "
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    • "CD is also routinely used to study the interaction of many flavonoids with biomolecules, providing valuable information on biomolecule-drug interaction, such as DNA binding of quercetin (Ahmadi et al., 2011), binding to serum albumin (di Bari et al., 2009) and hemoglobin (Chauduri et al., 2011), inhibition of β-amyloid toxicity and fibrillogenesis (Thapa et al., 2011). "
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