ArticleThe Journal of biological chemistry2013
Site-specific inhibitory mechanism for amyloid β42 aggregation by catechol-type flavonoids targeting the Lys residues.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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90 citing papers in PubMed, 228 citations in OpenAlex.
- Effect of the Tottori familial disease mutation (D7N) on the monomers and dimers of Aβ40 and Aβ42.ACS chemical neuroscience · 2013Trial
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- Covalent Modulation of Protein Misfolding and Aggregation Processes in the Context of Neurodegenerative Diseases.Archiv der Pharmazie · 2026Review
- Interactions Between Nutraceuticals and α-Synuclein Conformational States: Molecular Mechanisms and Neuroprotective Implications in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Effects of Cyanidin Derivatives for the Aggregation of Cu/Zn Superoxide Dismutase 1.ACS omega · 2026Article
- A facile and practical method for the synthesis ofBeilstein journal of organic chemistry · 2026Article
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- Lysine-Targeting Inhibitors of Amyloidogenic Protein Aggregation: A Promise for Neurodegenerative Proteinopathies.JACS Au · 2025Review
- Inhibition of amyloid formation of prion fragment (106-128) by polyphenolic compounds.Biochimica et biophysica acta. General subjects · 2025Article
- Plant-Based Inhibitors of Protein Aggregation.Biomolecules · 2025Review
- A Focus on the Link Between Metal Dyshomeostasis, Norepinephrine, and Protein Aggregation.Antioxidants (Basel, Switzerland) · 2025Review
- Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.Frontiers in chemistry · 2025Article
- Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.Frontiers in nutrition · 2025Article
- Molecular mechanisms of amyloid inhibition: an NMR-driven framework with polyphenols as a case study.Frontiers in molecular biosciences · 2025Article
- Cerebral amyloid angiopathy: a narrative review.Frontiers in aging neuroscience · 2025Review
- Molecular Signaling Pathways of Quercetin in Alzheimer's Disease: A Promising Arena.Cellular and molecular neurobiology · 2024Review
- Real-Time 3D Imaging and Inhibition Analysis of Human Serum Amyloid A Aggregations Using Quantum Dots.International journal of molecular sciences · 2024Article
- Neurotrophic Natural Products.Progress in the chemistry of organic natural products · 2024Article
- Synthesis of symmetrical and unsymmetrical tetrahydroxybiphenyls and their evaluation as amyloid-β aggregation inhibitors.Letters in organic chemistry · 2024Article
- Polyherbal and Multimodal Treatments: Kaempferol- and Quercetin-Rich Herbs Alleviate Symptoms of Alzheimer's Disease.Biology · 2023Review
30 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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