Site-specific inhibitory mechanism for amyloid β42 aggregation by catechol-type flavonoids targeting the Lys residues.

• Sato, Mizuho

• Murakami, Kazuma

• Uno, Mayumi

• Nakagawa, Yu

• Katayama, Sumie

• Akagi, Ken-ichi

• Masuda, Yuichi

• Takegoshi, Kiyonori

• Irie, Kazuhiro

Abstract

The aggregation of the 42-residue amyloid β-protein (Aβ42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aβ42 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 Aβ42 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 Aβ42-taxifolin adduct was suggested by mass spectrometry, Aβ42 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 Aβ42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Aβ42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-Aβ42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Aβ42 as well as Aβ42. Furthermore, interaction of (+)-taxifolin with the β-sheet region in Aβ42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Aβ42 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 Aβ42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.

Journal

• The Journal of biological chemistry

  The Journal of biological chemistry 288 (32), 23212-23224, 2013-08-09

  American Society for Biochemistry and Molecular Biology

Keywords

• Alzheimers Disease
• Amyloid
• Neurochemistry
• Oxidative Stress
• Protein Structure
• Aggregation
• Catechol
• Flavonoid
• Alzheimer Disease/drug therapy
• Alzheimer Disease/metabolism
• Amyloid/antagonists & inhibitors
• Amyloid/chemistry
• Amyloid/metabolism
• Amyloid beta-Peptides/antagonists & inhibitors
• Amyloid beta-Peptides/chemistry
• Amyloid beta-Peptides/metabolism
• Catechols/chemistry
• Catechols/metabolism
• Humans
• Lysine/chemistry
• Lysine/metabolism
• Norleucine/chemistry
• Norleucine/metabolism
• Peptide Fragments/antagonists & inhibitors
• Peptide Fragments/chemistry
• Peptide Fragments/metabolism
• Quercetin/analogs & derivatives
• Quercetin/chemistry
• Quercetin/metabolism

Details

• CRID: 1050845760727055104
• NII Article ID: 120005477416
• NII Book ID: AA00251083
• ISSN: 00219258
• HANDLE: 2433/190494
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles