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

被引:207
作者
Hyung, Suk-Joon [1 ]
DeToma, Alaina S. [1 ]
Brender, Jeffrey R. [1 ,2 ]
Lee, Sanghyun [3 ]
Vivekanandan, Subramanian [1 ,2 ]
Kochi, Akiko [1 ]
Choi, Jung-Suk [3 ]
Ramamoorthy, Ayyalusamy [1 ,2 ]
Ruotolo, Brandon T. [1 ]
Lim, Mi Hee [1 ,3 ]
机构
[1] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Biophys, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
amyloid-beta peptide; metal ions; natural products; amyloidogenesis; EPIGALLOCATECHIN GALLATE; ALZHEIMERS-DISEASE; FIBRIL FORMATION; ZINC-BINDING; AGGREGATION; EGCG; PEPTIDE; POLYPEPTIDE; COPPER; POLYPHENOLS;
D O I
10.1073/pnas.1220326110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:3743 / 3748
页数:6
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