Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 10, Pages 3743-3748Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220326110
Keywords
amyloid-beta peptide; metal ions; natural products; amyloidogenesis
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Funding
- National Institutes of Health [GM-084018, GM-095832]
- Alzheimer's Association New Investigator Research Grant [NIRG-10-172326]
- Alzheimer's Art Quilt Initiative
- American Heart Association
- Graduate Research Fellowship from the National Science Foundation
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Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-beta (metal-A beta) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-A beta species are necessary, along with a fundamental understanding of their mechanism at the molecular level. Herein, we investigated and compared the interactions and reactivities of the green tea extract, (-)-epigallocatechin-3-gallate [(2R,3R)-5,7-dihydroxy-2(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]-A beta and metal-free A beta species. We found that EGCG interacted with metal-A beta species and formed small, unstructured A beta aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metal-free A beta and metal-A beta was mitigated in living cells. To understand this reactivity at the molecular level, structural insights were obtained by ion mobility-mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. These studies indicated that (i) EGCG was bound to A beta monomers and dimers, generating more compact peptide conformations than those from EGCG-untreated A beta species; and (ii) ternary EGCG-metal-A beta complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal-A beta species with a structure-based mechanism.
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