Site-specific inhibitory mechanism for amyloid ?42 aggregation by catechol-type flavonoids targeting the Lys residues.

ABSTRACT: The aggregation of the 42-residue amyloid ?-protein (A?42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against A?42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of A?42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the A?42-taxifolin adduct was suggested by mass spectrometry, A?42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of A?42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of A?42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-A?42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-A?42 as well as A?42. Furthermore, interaction of (+)-taxifolin with the ?-sheet region in A?42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress A?42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of A?42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.

SUBMITTER: Sato M 

PROVIDER: S-EPMC3743493 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature