Inhibitory activity of stilbenes on Alzheimer’s β-amyloid fibrils in vitro

Rivière, Céline; Richard, Tristan; Quentin, Lysiane; Krisa, Stéphanie; Mérillon, Jean‐Michel; Monti, Jean‐Pierre

doi:10.1016/j.bmc.2006.09.069

Cited by 208 publications

(171 citation statements)

References 53 publications

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“…Synthesis of EGCG analogues (e.g., via combinatorial chemistry) may provide the answer to its structure-activity relationship and its greater potency over other anti-amyloidogenic polyphenols. 8,13,14,34 Moreover, analogues may be the solution to the challenges of stability, bioavailability and metabolic transformation that face the development of green tea polyphenols as therapeutic agents. 46 Although EGCG was unable to act as a β-sheet breaker (data not shown), the ability of future anti-aggregates to disrupt and destroy preformed amyloid fibrils, and thus reverse the fibrillation pathway, is an important goal.…”

Section: Discussionmentioning

confidence: 99%

“…8 These compounds constitute one of the most potent classes of anti-aggregation agents known to date. [8][9][10]13,14 In addition to their anti-amyloidogenic properties, these molecules possess potent anti-oxidant activity and a number of other beneficial health effects, such as anti-carcinogenic, anti-viral and anti-inflammatory properties. 8,15 Recently, (−)-epigallocatechin-3-gallate (EGCG) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

Hudson

Ecroyd

Dehle

et al. 2009

Journal of Molecular Biology

133

120

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The polyphenol (-)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-beta, alphasynuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer's, Parkinson's and Huntington's diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered offfolding pathway that results in the formation of non-toxic amorphous aggregates. whether this anti-fibril activity is specific to these disease-related target proteins or ismore generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMkappa-CN (reduced and carboxymethylated kappa-casein) and thereby protect pheochromocytoma-12 cells from RCMkappa-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation byRCMkappa-CN [the IC50 for 50 uM RCMkappa-CN is 1 uM]. Biophysical studies reveal that EGCG prevents RCMkappa-CN fibril formation by stabilising RCMkappa-CN in its nativelike state rather than by redirecting its aggregation to the disordered, amorphous aggregation pathway. Thus, while it appears that EGCG is a generic inhibitor of amyloid-fibril formation, the mechanism by which it achieves this inhibition is specific to the target fibril-forming polypeptide. It is proposed that EGCG is directed to the amyloidogenic sheet-turn-sheet motif of monomeric RCMkappa-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent pi-pi stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated. The polyphenol (−)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-β, α-synuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer's, Parkinson's and Huntington's diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered off-folding pathway that results in the formation of non-toxic amorphous aggregates. Whether this anti-fibril activity is specific to these disease-related target proteins or is more generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMκ-CN (reduced and carboxymethylated κ-casein) and thereby protect pheochromocytoma-12 cells from RCMκ-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation by RCMκ-CN [the IC 50 for 50 μM RCMκ-CN is 13 ± 1 μM]. Biophys...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

Hudson

Ecroyd

Dehle

et al. 2009

Journal of Molecular Biology

133

120

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“…This inhibition coincided with attenuation of Alzheimer's disease-type cognitive impairment. Resveratrol and its glucoside, piceid, have, however, been shown in vitro to dose-dependently inhibit the formation of A␤ fibrils [134,135]; other stilbene monomers examined are less potent inhibitors. Binding may be induced by hydrophobic interactions between the phenolic rings and the hydrophobic region of A␤, thus blocking associations between A␤ molecules and inhibiting fibril formation.…”

Section: Amyloid-β Factors and Alzheimer's Diseasementioning

confidence: 94%

Wine consumption, cognitive function and dementias – A relationship?

Stockley

2016

NUA

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Abstract. Healthy cognitive function is essential for quality of life, wellbeing and independent living, and is negatively associated with dementias. A series of longitudinal and neuro-imaging studies in the elderly have shown that light to moderate wine consumption is neuro-protective although heavy or abusive alcohol consumption is neuro-toxic. A J-shaped relationship between alcohol consumption, cognitive dysfunction and risk of dementias is also observed for younger and middle aged consumers. There is also no data to suggest that long-term light to moderate alcohol consumption exacerbates age-related cognitive decline and impairment. An optimal amount of wine for neuro-protection appears to be up to 30 g alcohol daily.There are multiple plausible biological mechanisms in various animal models, in vitro and in vivo for wine-derived phenolic compounds which go beyond their antioxidant activity and attenuation of oxidative stress.

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“…By itself, resveratrol is a potent anti-oxidant which is thought to be responsible for the French Paradox [65]; relating to the low incidence of cardiovascular disease in a French population with high intake of saturated fats. In addition to its demonstrated capacity to inhibit (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fibril formation in vitro [16], resveratrol is also capable of promoting intracellular uptake and degradation of through a proteosome-dependent mechanism [66] and protecting against -induced neurotoxicity [67,68], possibly through activation of the NAD-dependent histone deacetylase, SIRT1 [69]. In the present study using the ELISA-based assay, catechin showed no inhibitory activity during the early stages of oligomerization, whereas rosmarinic acid demonstrated some activity at the highest concentration tested.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, prevention of aggregation has been explored through the identification of small molecule inhibitors [15]. From these efforts, a number of useful lead compounds have been identified such as sulfonated anions, benzofuran derivatives, as well as other polyphenolbased compounds [16][17][18][19][20]. Evaluations of these lead compounds have utilized various methodologies including differential centrifugation, light scattering, fluorescent spectral shifts and SDS-PAGE mobility shifts [21], all of which measure large molecular aggregates of peptide.…”

Section: Introductionmentioning

confidence: 99%

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

Gonzales¹,

Orlando²

2009

TOBIOTJ

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Amyloid deposits found in Alzheimer's disease result from aggregation of peptide which leads to loss of synaptic function, chronic microglial activation and cognitive impairment. Because of this, identification of small molecule inhibitors of aggregation as potential therapeutics is a topic of current interest. The majority of inhibitor screening approaches rely on in vitro assays that lack the necessary sensitivity to distinguish low-molecular weight oligomers from larger, more advanced-stage fibrillar structures. Differentiating between these two structures is of vital concern since recent studies indicate that small, early-stage oligomers are the most neurotoxic form of peptide aggregate. To address this limitation, we have explored the adaptability of a recently described ELISA-based assay for discovery of small molecule inhibitors of oligomerization. Results show that this assay is highly sensitive as it is able to quantify oligomers with as little as 80 nM input peptide. In addition, data were obtained re-confirming the function of curcumin as a potent inhibitor of aggregation (IC 50 = 2 μM) and defining its inhibitor:peptide functional stoichiometry. Further examination of other known anti-aggregation compounds showed that this assay is able to discriminate between inhibitors of early-stage, low-molecular weight oligomers and later-stage, high-molecular weight fibrillar structures. These findings indicate that this new ELISA-based assay is capable of identifying novel small molecule inhibitors that function during the initial stages of peptide assembly.

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Inhibitory activity of stilbenes on Alzheimer’s β-amyloid fibrils in vitro

Cited by 208 publications

References 53 publications

(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

Wine consumption, cognitive function and dementias – A relationship?

A Sensitive Aβ Oligomerization Assay for Identification of Small Molecule Inhibitors

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