The Effect of (−)-Epigallocatechin-3-Gallate on the Amyloid-β Secondary Structure

Abstract

Amyloid-b (Ab) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies targeting amyloids. In this study, we investigate the interactions of epigallocatechin-3-gallate (EGCG), found in green tea, with Ab polypeptides, using a combination of in vitro immuno-infrared sensor measurements, docking, molecular dynamics simulations, and ab initio calculations. We find that the interactions of EGCG are dominated by only a few residues in the fibrils, including hydrophobic p-p interactions with aromatic rings of side chains and hydrophilic interactions with the backbone of Ab, as confirmed by extended (1-ms-long) molecular dynamics simulations. Immuno-infrared sensor data are consistent with degradation of Ab fibril induced by EGCG and inhibition of Ab fibril and oligomer formation, as manifested by the recovery of the amide-I band of monomeric Ab, which is red-shifted by 26 cm À1 when compared to the amide-I band of the fibrillar form. The shift is rationalized by computations of the infrared spectra of Ab42 model structures, suggesting that the conformational change involves interchain hydrogen bonds in the amyloid fibrils that are broken upon binding of EGCG.

(−)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer’s Disease PSEN1 E280A

“…However, further investigation is needed to confirm this assumption. Specifically, mounting evidence has shown that EGCG inhibits the oligomerization of Aβ42 [ 41 , 42 , 43 ]. Consistent with previous work [ 21 ], we found that EGCG induces highly stable aggregates of synthetic Aβ42.…”

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

“…This same lysine also interacted with the gallic acid of EGCG, confirming that group’s critical role in protofibril disruption ( Zhan et al, 2020 ). Thus, it was observed that the central interference promoted by EGCG in fibril formation is the disruption of inter-chain hydrogen bonds and salt bridges crucial to amyloid structure ( Acharya et al, 2020 ). Even though the mechanism of action of EGCG has not been elucidated, the knowledge of some forms of interaction between the compound and amyloid proteins can generate valuable information for therapeutic strategies against aggregation.…”

“…The aromatic rings, hydroxyls groups and gallate motif of EGCG appear to be essential for the interactions with proteins and the anti-amyloid effectiveness ( Rambold et al, 2008 ; Sironi et al, 2014 ; Fusco et al, 2018 ). Moreover, the hydrophobic interactions and hydrogen bonds represent the main form of protein-compound interaction, resulting in inhibition of the conversion in β amyloid toxic structures ( Wang et al, 2010 ), and the break of saline bridges promoted by EGCG can be crucial to interrupt the fibril structuration ( Acharya et al, 2020 ; Yao et al, 2020 ; Zhan et al, 2020 ).…”

Destabilization potential of beta sheet breaker peptides on Abeta fibril structure: an insight from molecular dynamics simulation study

“…[55][56][57][58] Abeta being polymorphic in nature each of the bril structure have its own importance and which have been highlighted in the recent experimental and computational studies. [59][60][61][62][63] Also, studies by Cheon M et al 62 & Kahler A et al 63 suggest formation of U-shaped brillar structure from potent on-pathway intermediates of the Ab17-42 pentamer and hexamer oligomers (paranuclei). The U-shaped model (2BEG) has been part of most of the previously reported molecular simulation studies.…”