Green tea extracts interfere with the stress‐protective activity of PrP<sup>C</sup> and the formation of PrP<sup>Sc</sup>

Rambold, Angelika S.; Miesbauer, Margit; Olschewski, Diana; Seidel, R.; Riemer, Constanze; Smale, Lindsay; Brumm, Lisa; Levy, Michal; Gazit, Ehud; Oesterhelt, Dieter; Baier, Michael; Becker, Christian F. W.; Engelhard, Martin; Winklhofer, Konstanze F.; Tatzelt, Jörg

doi:10.1111/j.1471-4159.2008.05611.x

Cited by 65 publications

(83 citation statements)

References 56 publications

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“…It is therefore also feasible that EGCG has the capacity to break up pre-formed fibrils; this would support our findings of attenuated toxicity of PC12 cells when incubated with pre-formed fibrillar Ab protein together with EGCG, and the results of the TEM experiments where preformed fibril and aggregate formation was directly disrupted by EGCG. This remarkable property of EGCG is a finding similarly observed for both amyloid-b and a-synuclein in EGCGtreated PC12 cells (Bieschke et al, 2010) and for other forms of pathogenic amyloid-b proteins (Chandrashekaran et al, 2010;Hauber, Hohenberg, Holstermann, Hunstein, & Hauber, 2009;Rambold et al, 2008). EGCG also displays anti-amyloid efficacy following in vivo oral dosing, suggesting it has a favourable bioavailability to act as an orally available amyloid-b fibril-disrupting agent (Lee et al, 2009).…”

Section: Discussionmentioning

confidence: 59%

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

et al. 2011

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Section: Discussionmentioning

confidence: 59%

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

et al. 2011

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“…As with any such phenotypic screening follow-up cascade, elucidating the precise mechanism of action required the development of several specific and general assays that flag spurious promiscuous binders. This was exemplified by the two natural trihydroxyphenyl compounds from tea that have been linked to a number of health benefits through their interactions with various protein targets (Mori et al, 2010;Palhano et al, 2013;Rambold et al, 2008). Autooxidation of the gallyl and gallate moieties within EGCG and TG can create reactive species that react with cysteine thiol groups (Ishii et al, 2008) and/or free amines in proteins (Palhano et al, 2013).…”

Section: Discussionmentioning

confidence: 97%

Small Molecule Inhibitors of Clostridium difficile Toxin B-Induced Cellular Damage

Tam

Beilhartz

Auger

et al. 2015

Chemistry & Biology

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Clostridium difficile causes life-threatening diarrhea through the actions of its homologous toxins TcdA and TcdB on human colonocytes. Therapeutic agents that block toxin-induced damage are urgently needed to prevent the harmful consequences of toxin action that are not addressed with current antibiotic-based treatments. Here, we developed an imaging-based phenotypic screen to identify small molecules that protected human cells from TcdB-induced cell rounding. A series of structurally diverse compounds with antitoxin activity were identified and found to act through one of a small subset of mechanisms, including direct binding and sequestration of TcdB, inhibition of endosomal maturation, and noncompetitive inhibition of the toxin glucosyltransferase activity. Distinct classes of inhibitors were used further to dissect the determinants of the toxin-mediated necrosis phenotype occurring at higher doses of toxin. These findings validate and inform novel targeting strategies for discovering small molecule agents to treat C. difficile infection.

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“…Alzheimer | Parkinson | catechine | misfolding | oligomer P revious studies have shown that the polyphenol (-)-epi-gallocatechine gallate (EGCG), found in large amounts in green tea, has antiamyloidogenic properties and modulates the misfolding of disease proteins and prions (1)(2)(3)(4)(5). EGCG directly binds to unfolded polypeptide chains and inhibits β-sheet formation, an early event in the amyloid formation cascade (6).…”

mentioning

confidence: 99%

EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

Bieschke

Russ

Friedrich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

911

926

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Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer's and Parkinson's disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheetrich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.Alzheimer | Parkinson | catechine | misfolding | oligomer P revious studies have shown that the polyphenol (-)-epi-gallocatechine gallate (EGCG), found in large amounts in green tea, has antiamyloidogenic properties and modulates the misfolding of disease proteins and prions (1-5). EGCG directly binds to unfolded polypeptide chains and inhibits β-sheet formation, an early event in the amyloid formation cascade (6). In the presence of EGCG, the assembly of a new type of unstructured, SDSstable, nontoxic oligomer was observed, instead of the expected formation of β-sheet-rich aggregates. This suggested that the compound redirects aggregation prone polypeptides into offpathway protein assemblies (6), as has since been confirmed for other flavonoids (7).These findings raise the question of whether EGCG might also be able to disassemble preformed, β-sheet-rich structures as well as earlier intermediates of fibrillogenesis. Other small molecules such as curcumin or short β-sheet breaker peptides were described to have this ability; however, their mechanism of action has not been elucidated (8,9). In the present study, we examined the ability of EGCG to alter the structure of mature amyloid fibrils with biochemical and biophysical as well as cell-based assays. Results and DiscussionTo study the effect of EGCG on preformed amyloid aggregates, we first produced α-synuclein (αS) fibrils by incubating natively unfolded monomers (100 μM) at 37°C for 7 d in phosphate buffer. Then aggregates were characterized by EM, atomic force microscopy (AFM), Thioflavin T (ThT) binding assays, and CD spectroscopy (Fig. S1). We observed that the in vitro generated αS aggregates have a β-sheet structure and a fibrillar morphology. Moreover, they efficiently bind the dye ThT, supporting previously published results (10).Next, we added an equimolar concentration of EGCG to the fibrils (50 μM αS monomer equivalent). The effect of the compound was monitored by time-resolved EM and AFM. We found that EGCG very efficiently remodels the ordered, fibrillar morphology ...

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Green tea extracts interfere with the stress‐protective activity of PrP^C and the formation of PrP^Sc

Cited by 65 publications

References 56 publications

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

Small Molecule Inhibitors of Clostridium difficile Toxin B-Induced Cellular Damage

EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

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Green tea extracts interfere with the stress‐protective activity of PrPC and the formation of PrPSc

Cited by 65 publications

References 56 publications

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

The green tea polyphenol (−)-epigallocatechin-3-gallate inhibits amyloid-β evoked fibril formation and neuronal cell death in vitro

Small Molecule Inhibitors of Clostridium difficile Toxin B-Induced Cellular Damage

EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

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Green tea extracts interfere with the stress‐protective activity of PrP^C and the formation of PrP^Sc