title: Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate toward metal-associated amyloid-β species.
abstract: 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)-3,4-dihydro-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 metal-free 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 dimers, generating more compact peptide conformations than those from EGCG-untreated 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 structure-based mechanism.
authors: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Suk-Joon
authors: SJ
authors: Hyung
authors: Alaina S
authors: AS
authors: DeToma
authors: Jeffrey R
authors: JR
authors: Brender
authors: Sanghyun
authors: S
authors: Lee
authors: Subramanian
authors: S
authors: Vivekanandan
authors: Akiko
authors: A
authors: Kochi
authors: Jung-Suk
authors: JS
authors: Choi
authors: Ayyalusamy
authors: A
authors: Ramamoorthy
authors: Brandon T
authors: BT
authors: Ruotolo
authors: Mi Hee
authors: MH
authors: Lim
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000187:drug effects* / Q000633:toxicity; D028241:Camellia sinensis / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008670:Metals / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects / Q000633:toxicity; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D016229:Amyloid beta-Peptides; D008670:Metals; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010936:Plant Extracts; C078592:amyloid beta-protein (1-40); D003300:Copper; D002392:Catechin; C045651:epigallocatechin gallate; D015032:Zinc