The Effect of (−)-Epigallo-catechin-(3)-gallate on Amyloidogenic Proteins Suggests a Common Mechanism

Abstract

Studies on the interaction of the green tea polyphenol (−)-Epigallocatechin-3-gallate (EGCG) with fourteen disease-related amyloid polypeptides and prions Huntingtin, Amyloid-beta, alpha-Synuclein, islet amyloid polypeptide (IAPP), Sup35, NM25 and NM4, tau, MSP2, semen-derived enhancer of virus infection (SEVI), immunoglobulin light chains, beta-microglobulin, prion protein (PrP) and Insulin, have yielded a variety of experimental observations. Here, we analyze whether these observations could be explained by a common mechanism and give a broad overview of the published experimental data on the actions of EGCG. Firstly, we look at the influence of EGCG on aggregate toxicity, morphology, seeding competence, stability and conformational changes. Secondly, we screened publications elucidating the biochemical mechanism of EGCG intervention, notably the effect of EGCG on aggregation kinetics, oligomeric aggregation intermediates, and its binding mode to polypeptides. We hypothesize that the experimental results may be reconciled in a common mechanism, in which EGCG binds to cross-beta sheet aggregation intermediates. The relative position of these species in the energy profile of the amyloid cascade would determine the net effect of EGCG on aggregation and disaggregation of amyloid fibrils.

Aggregation of Full-length Immunoglobulin Light Chains from Systemic Light Chain Amyloidosis (AL) Patients Is Remodeled by Epigallocatechin-3-gallate

“…Compounds like EGCG can inhibit amyloid formation in a wide variety of misfolded proteins in vitro and in animal models (57). Preliminary evidence suggests that EGCG may counteract amyloid deposition in AL patients and improve their prognosis (34,35,58).…”

“…When systematically reviewing EGCG mechanisms in various proteins, we found that EGCG binding to aggregation intermediates may inhibit amyloid formation very effectively in cases where these species are rate-limiting to amyloid formation (57). In other cases, amyloid formation is dominated by a structural transition or dissociation of the native protein.…”

“…In other cases, amyloid formation is dominated by a structural transition or dissociation of the native protein. Here, EGCG may bind to native proteins and have less of an effect on kinetics but may nevertheless divert the protein into stable non-amyloid aggregates (57).…”

Zinc Boosts EGCG’s hIAPP Amyloid Inhibition Both in Solution and Membrane

“…[7] One of the frequently investigated amyloid inhibitors is epigallocatechin-gallate (EGCG; the major catechin present in green tea) ( Fig.S1B), a polyphenolic compound found in green tea extract. [8][9][10][11][12] EGCG has been shown to be an effective amyloid inhibitor for a variety of amyloid-forming peptides and proteins. In addition to small molecule modulation, metal ions were shown to play a role in amyloid aggregation.…”

Characterizing the inhibition of α‐synuclein oligomerization by a pharmacological chaperone that prevents prion formation by the protein PrP

“…[38][39][40][41] Particularly interesting among these inhibitors are cyclic tetrapyrroles and related molecules (e.g., porphyrins, phthalocyanines, and corrins), which have been shown to modify the aggregation of multiple proteins exhibiting prion-like propagated misfolding, including Aβ, 42,43 tau, 44,45 and prion protein (PrP). [46][47][48][49][50][51] In some cases, these compounds are proposed to stabilize off-pathway oligomers, 52,53 whereas in others, they are proposed to stabilize monomers 54 or interfere with interactions stabilizing larger aggregates, 55 but in most cases, their mechanism of action is incompletely understood.…”