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: 3.02).
02/2011; 50(13):2445-55. DOI: 10.1021/bi101731d
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.
Available from: PubMed Central
- "Human amyloid proteins (Aβ) are peptides of rather 39-42 residues. Aβ40 contains 40 amino acids and Aβ42 is the major isoform in the Aβ peptides with 42 residues polypeptide chain and it is the responsible of amyloid plaques generated in Alzheimer’s disorder [15,16]. "
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ABSTRACT: Backgrounds: The process of amyloid proteins aggregation causes several human neuropathologies. In some cases, e.g. fibrillar deposits of insulin, the problems are generated in the processes of production and purification of protein and in the pump devices or injectable preparations for diabetics. Experimental kinetics and adequate modelling of chemical inhibition from amyloid aggregation are of practical importance in order to study the viable processing, formulation and storage as well as to predict and optimize the best conditions to reduce the effect of protein nucleation.
In this manuscript, experimental data of insulin, Abeta42 amyloid protein and apomyoglobin fibrillation from recent bibliography were selected to evaluate the capability of a bivariate sigmoid equation to model them. The mathematical functions (logistic combined with Weibull equation) were used in reparameterized form and the effect of inhibitor concentrations on kinetic parameters from logistic equation were perfectly defined and explained. The surfaces of data were accurately described by proposed model and the presented analysis characterized the inhibitory influence on the protein aggregation by several chemicals. Discrimination between true and apparent inhibitors was also confirmed by the bivariate equation. EGCG for insulin (working at pH = 7.4/T = 37[degree sign]C) and taiwaniaflavone for Abeta42 were the compounds studied that shown the greatest inhibition capacity.
An accurate, simple and effective model to investigate the inhibition of chemicals on amyloid protein aggregation has been developed. The equation could be useful for the clear quantification of inhibitor potential of chemicals and rigorous comparison among them.
Available from: Jing-Ke Weng
- "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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ABSTRACT: Early plants began colonizing the terrestrial earth approximately 450 million years ago. Their success on land has been partially attributed to the evolution of specialized metabolic systems from core metabolic pathways, the former yielding structurally and functionally diverse chemicals to cope with a myriad of biotic and abiotic ecological pressures. Over the past two decades, functional genomics, primarily focused on flowering plants, has begun cataloging the biosynthetic players underpinning assorted classes of plant specialized metabolites. However, the molecular mechanisms enriching specialized metabolic pathways during land plant evolution remain largely unexplored. Selaginella is an extant lycopodiophyte genus representative of an ancient lineage of tracheophytes. Notably, the lycopodiophytes diverged from euphyllophytes over 400 million years ago. The recent completion of the whole-genome sequence of an extant lycopodiophyte, S. moellendorffii, provides new genomic and biochemical resources for studying metabolic evolution in vascular plants. 400 million years of independent evolution of lycopodiophytes and euphyllophytes resulted in numerous metabolic traits confined to each lineage. Surprisingly, a cadre of specialized metabolites, generally accepted to be restricted to seed plants, have been identified in Selaginella. Initial work suggested that Selaginella lacks obvious catalytic homologs known to be involved in the biosynthesis of well-studied specialized metabolites in seed plants. Therefore, these initial functional analyses suggest that the same chemical phenotypes arose independently more commonly than anticipated from our conventional understanding of the evolution of metabolism. Notably, the emergence of analogous and homologous catalytic machineries through convergent and parallel evolution, respectively, seems to have occurred repeatedly in different plant lineages.
Available from: Sharoar MG
- "The accumulated species were soluble and relatively smaller in size than toxic oligomers (Figure 5A), devoid of β-sheet fibrillar form (Figures 3F and 5B) and less toxic (Figure 5C), indicating that they might not be the “on pathway” aggregates. The findings are in good agreement with those of previous studies, where polyphenol (−)-epigallocatechin gallate and taiwniaflavone were found to be effective in inhibition of fibrillogenesis of Aβ by directly binding to the unfolded polypeptides and promoted formation of unstructured and nontoxic, off pathway, stable oligomeric structures [39,45]. The K-3-rh and other related flavonoids used in the current study probably redirected the Aβ assembly in similar way to form non toxic off-pathway intermediated structure. "
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Aggregation of soluble, monomeric β- amyloid (Aβ) to oligomeric and then insoluble fibrillar Aβ is a key pathogenic feature in development of Alzheimer’s disease (AD). Increasing evidence suggests that toxicity is linked to diffusible Aβ oligomers, rather than to insoluble fibrils. The use of naturally occurring small molecules for inhibition of Aβ aggregation has recently attracted significant interest for development of effective therapeutic strategies against the disease. A natural polyphenolic flavone, Kaempferol-3-O-rhamnoside (K-3-rh), was utilized to investigate its effects on aggregation and cytotoxic effects of Aβ42 peptide. Several biochemical techniques were used to determine the conformational changes and cytotoxic effect of the peptide in the presence and absence of K-3-rh.
K-3-rh showed a dose-dependent effect against Aβ42 mediated cytotoxicity. Anti-amyloidogenic properties of K-3-rh were found to be efficient in inhibiting fibrilogenesis and secondary structural transformation of the peptide. The consequence of these inhibitions was the accumulation of oligomeric structural species. The accumulated aggregates were smaller, soluble, non-β-sheet and non-toxic aggregates, compared to preformed toxic Aβ oligomers. K-3-rh was also found to have the remodeling properties of preformed soluble oligomers and fibrils. Both of these conformers were found to remodel into non-toxic aggregates. The results showed that K-3-rh interacts with different Aβ conformers, which affects fibril formation, oligomeric maturation and fibrillar stabilization.
K-3-rh is an efficient molecule to hinder the self assembly and to abrogate the cytotoxic effects of Aβ42 peptide. Hence, K-3-rh and small molecules with similar structure might be considered for therapeutic development against AD.
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