Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid-β species

Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-β (metal-Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-Aβ species are necessary, along with a fundamental...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2013-03, Vol.110 (10), p.3743-3748
Main Authors: Hyung, Suk-Joon, DeToma, Alaina S., Brender, Jeffrey R., Lee, Sanghyun, Vivekanandan, Subramanian, Kochi, Akiko, Choi, Jung-Suk, Ramamoorthy, Ayyalusamy, Ruotolo, Brandon T., Lim, Mi Hee
Format: Article
Language:English
Subjects:
Aggregation
Alzheimer Disease - etiology
Alzheimer Disease - metabolism
Alzheimer Disease - prevention & control
Alzheimers disease
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - drug effects
Amyloid beta-Peptides - toxicity
Amyloids
Biological Sciences
Camellia sinensis - chemistry
Catechin - analogs & derivatives
Catechin - chemistry
Catechin - pharmacology
Cell aggregates
Copper - chemistry
Copper - pharmacology
Copper - toxicity
Dimers
Humans
Metal aggregates
Metal ions
Metals - chemistry
Metals - pharmacology
Metals - toxicity
Models, Molecular
Monomers
Neuroprotective Agents - chemistry
Neuroprotective Agents - pharmacology
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments - chemistry
Peptide Fragments - drug effects
Peptide Fragments - toxicity
Physical Sciences
Plant Extracts - chemistry
Plant Extracts - pharmacology
Protein Binding
Protein Conformation - drug effects
Protein Multimerization - drug effects
Reactivity
Solar fibrils
Tandem Mass Spectrometry
Zinc - chemistry
Zinc - pharmacology
Zinc - toxicity
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Description
Summary:Despite the significance of Alzheimer's disease, the link between metal-associated amyloid-β (metal-Aβ) and disease etiology remains unclear. To elucidate this relationship, chemical tools capable of specifically targeting and modulating metal-Aβ 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)-3,4HJihydro-2H-1-benzopyran-3-yl 3,4,5-trihydroxybenzoate; EGCG], with metal [Cu(II) and Zn(II)]-Aβ and metal-free Aβ species. We found that EGCG interacted with metal-Aβ species and formed small, unstructured Aβ aggregates more noticeably than in metal-free conditions in vitro. In addition, upon incubation with EGCG, the toxicity presented by metalfree Aβ and metal-Aβ 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 Aβ monomers and dinners, generating more compact peptide conformations than those from EGCGuntreated Aβ species; and (ii) ternary EGCG-metal-Aβ complexes were produced. Thus, we demonstrate the distinct antiamyloidogenic reactivity of EGCG toward metal-Aβ species with a structurebased mechanism.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1220326110