Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains

Hora, Manuel; Carballo-Pacheco, Martín; Weber, Benedikt; Morris, Vanessa K.; Wittkopf, Antje; Büchner, Johannes; Strodel, Birgit; Reif, Bernd

doi:10.1038/srep41515

Cited by 23 publications

(20 citation statements)

References 88 publications

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“…Due to the binding of EGCG, the conformation of hIAPP changes: the intra- and intermolecular interactions of hIAPP responsible for β-sheet formation are decreased. A similar mechanism was already proposed for amyloid-β, α-synuclein and immunoglobulin light chain, in which amorphous aggregates are formed in the presence of EGCG as non-toxic species showing a reduced degree of structural homogeneity 9 , 10 , 39 , 40 . In the hIAPP structural analysis 25 , no intermolecular NOE (nuclear Overhauser effect) contacts have been observed, suggesting that the major conformer in our study is monomeric.…”

Section: Discussionsupporting

confidence: 63%

Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

Frankó

Camargo

Böddrich

et al. 2018

Sci Rep

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The formation of amyloid fibrils by human islet amyloid polypeptide protein (hIAPP) has been implicated in pancreas dysfunction and diabetes. However, efficient treatment options to reduce amyloid fibrils in vivo are still lacking. Therefore, we tested the effect of epigallocatechin gallate (EGCG) on fibril formation in vitro and in vivo. To determine the binding of hIAPP and EGCG, in vitro interaction studies were performed. To inhibit amyloid plaque formation in vivo, homozygous (tg/tg), hemizygous (wt/tg), and control mice (wt/wt) were treated with EGCG. EGCG bound to hIAPP in vitro and induced formation of amorphous aggregates instead of amyloid fibrils. Amyloid fibrils were detected in the pancreatic islets of tg/tg mice, which was associated with disrupted islet structure and diabetes. Although pancreatic amyloid fibrils could be detected in wt/tg mice, these animals were non-diabetic. EGCG application decreased amyloid fibril intensity in wt/tg mice, however it was ineffective in tg/tg animals. Our data indicate that EGCG inhibits amyloid fibril formation in vitro and reduces fibril intensity in non-diabetic wt/tg mice. These results demonstrate a possible in vivo effectiveness of EGCG on amyloid formation and suggest an early therapeutical application.

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Section: Discussionsupporting

confidence: 63%

Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

Frankó

Camargo

Böddrich

et al. 2018

Sci Rep

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“…3(c), unlike IDPs such as Aβ or amyloidogenic proteins with low-complexity sequences. Recent progress is particularly notable in the previously poorly served (by ssNMR) area of light chain amyloidosis research with very recent work on two light chain variants [95–97]. The study of the variable domain of AL-09 included a comparison to patient-derived material, based not on the seeding of labeled protein, but rather the direct acquisition of patient material’s natural abundance 13 C spectrum.…”

Section: Protein Aggregation In Human Diseasementioning

confidence: 99%

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

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The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation. A central focus is on disease-related amyloid fibrils and oligomers involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. SSNMR-enabled structural and dynamics-based findings are surveyed, along with a number of resulting emerging themes that appear common to different amyloidogenic proteins, such as their compact alternating short-β-strand/β-arc amyloid core architecture. Concepts, methods, future prospects and challenges are discussed.

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Lin

Cox

et al. 2018

Preprint

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Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to insulin-producing islet cell death in type II diabetes. Previous studies have shown the amyloid inhibiting effects of zinc (Zn) and insulin that are co-present with hIAPP in islet cells, and the lipid membrane has been shown to significantly influence the aggregation kinetics. Increasing number of studies report the importance of developing small molecule inhibitors to suppress the hIAPP's toxicity.Particularly, the ability of epigallocatechin-gallate (EGCG) to inhibit amyloid aggregation of a variety of amyloid peptide/proteins including hIAPP initiated numerous studies including the development of compounds to potentially treat amyloid diseases. In this study, by using a combination of thioflavin-T fluorescence and transmission electron microscopy experiments, we demonstrate a significant enhancement in EGCG's efficiency, when mixed with Zn, to significantly suppress hIAPP amyloid aggregation both in presence and absence of lipid membrane. Circular dichroism experiments indicate the formation and stabilization of a helical structure of hIAPP in presence of EGCG:Zn complex. Our results also reveal the ability of EGCG or EGCG:Zn to suppress hIAPP's cellular toxicity and that the ability of EGCG to chelate with Zn suppresses zinc's cellular toxicity. We suggest that the reported results would be useful to develop strategies to trap hIAPP intermediates for further biophysical and structural studies, and also to devise approaches to abolish amyloid aggregation and cellular toxicity.

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Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains

Cited by 23 publications

References 88 publications

Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

Epigallocatechin gallate (EGCG) reduces the intensity of pancreatic amyloid fibrils in human islet amyloid polypeptide (hIAPP) transgenic mice

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

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

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