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Lim, Mi Hee
MetalloNeuroChemistry Lab (MNCL)
Research Interests
  • Neurodegenerative disease, small molecule design, network between metal, proteins, and ROS

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Effects of hydroxyl group variations on a flavonoid backbone toward modulation of metal-free and metal-induced amyloid-β aggregation

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Title
Effects of hydroxyl group variations on a flavonoid backbone toward modulation of metal-free and metal-induced amyloid-β aggregation
Author
Lee, HyuckjinKerr, Richard A.Korshavn, Kyle J.Lee, JeeyeonKang, JuhyeRamamoorthy, AyyalusamyRuotolo, Brandon T.Lim, Mi Hee
Keywords
MOBILITY-MASS SPECTROMETRY; ALZHEIMERS-DISEASE; SMALL MOLECULES; FIBRIL FORMATION; REACTIVITY; COMPLEXES; PROTEIN; OXIDATION; QUERCETIN; BINDING
Issue Date
201603
Publisher
Inorganic Chemistry Frontiers
Citation
INORGANIC CHEMISTRY FRONTIERS, v.3, no.3, pp.381 - 392
Abstract
Amyloid-β (Aβ) and metal ions are suggested to be involved in the pathogenesis of Alzheimer’s disease(AD). Cu(II) and Zn(II) can interact with Aβ and facilitate peptide aggregation producing toxic oligomeric peptide species. Additionally, redox-active metal-bound Aβ is shown to generate reactive oxygen species(ROS). Although the interaction of metal ions with Aβ and the reactivity of metal-associated Aβ (metal–Aβ) are indicated, the relationship between metal–Aβ and AD etiology is still unclear. Some naturally occurring flavonoids capable of redirecting metal–Aβ peptides into nontoxic, off-pathway Aβ aggregates have been presented as valuable tools for elucidating the role of metal–Aβ in AD. The structural moieties of the flavonoids responsible for their reactivity toward metal–Aβ are not identified, however. To determine a structure–interaction–reactivity relationship between flavonoids and metal-free Aβ or metal–Aβ, four flavonoids (morin, quercetin, galangin, and luteolin) were rationally selected based on structural variations(i.e., number and position of hydroxyl groups). These four flavonoids could noticeably modulate metal–Aβ aggregation over metal-free analogue to different extents. Moreover, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) studies reveal that the direct interactions of the flavonoids with metal-free and/or metal-bound Aβ are distinct. Overall, our studies demonstrate that alternation of the hydroxyl groups on the B and C rings of flavonoids (structure) could differentiate their metal/metal-free Aβ/metal–Aβ interactions (interaction) and subsequently direct their effects on metal-free Aβ and metal–Aβ aggregation in vitro and Aβ–/metal–Aβ-triggered toxicity in living cells (reactivity), suggesting a structure–interaction–reactivity relationship.
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DOI
http://dx.doi.org/10.1039/c5qi00219b
ISSN
2052-1553
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