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Inhibiting amyloid ?-protein assembly: Size-activity relationships among grape seed-derived polyphenols.

ABSTRACT: Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of A? in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractionate the mixture into monomers, dimers, and oligomers. Each fraction was analyzed for its effect on A? conformational dynamics (circular dichroism), oligomerization (zero-length photochemical cross-linking), aggregation kinetics (Thioflavin T fluorescence), and morphology (electron microscopy). The relative activities of each fraction were determined on the basis of molar concentration (mol/L) or mass concentration (g/L). When molar concentration, the number concentration of each polyphenolic compound, was considered, the oligomer fraction was the most potent inhibitor of A? oligomerization and aggregation. However, when mass concentration, the number concentration of phenolic groups, was considered, monomers were the most potent inhibitors. To understand these ostensibly contradictory results, a model of polyphenol:A? complexation was developed. This model, which was found to be consistent with published X-ray crystallographic studies, offers an explanation for the effects of functional group polyvalency on inhibitor activity. Our data emphasize the importance of an in-depth understanding of the mechanism(s) underlying 'concentration dependence' in inhibitor systems involving polyfunctional agents.

SUBMITTER: Hayden EY

PROVIDER: S-EPMC5639934 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Inhibiting amyloid β-protein assembly: Size-activity relationships among grape seed-derived polyphenols.

Hayden Eric Y EY Yamin Ghiam G Beroukhim Shiela S Chen Benson B Kibalchenko Mikhail M Jiang Lin L Ho Lap L Wang Jun J Pasinetti Giulio M GM Teplow David B DB

Journal of neurochemistry 20150902 2

Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Aβ in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractiona ...[more]

PMID: 26228682

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Project description:White adipose tissue (WAT) expands through hypertrophy (increased adipocyte size) and/or hyperplasia (increased adipocyte number). Hypertrophy has been associated with insulin resistance and dyslipidemia independently of body composition and fat distribution. In contrast, hyperplasia protects against metabolic alterations. Proanthocyanidins, which are the most abundant flavonoids in the human diet, improve metabolic disturbances associated with diet-induced obesity without reducing body weight or adiposity. The aim of this study was to determine whether grape seed proanthocyanidin extract (GSPE) can modulate WAT expandability. Because GSPE also contains gallic acid, we also studied the capacity of gallic acid to remodel WAT.Male Wistar rats were fed a standard chow diet (n=6) or a cafeteria diet (CAF) for 11 weeks. After 8 weeks, the CAF-fed animals were supplemented with 25?mg GSPE/kg body weight (n=6), 7?mg gallic acid/kg body weight (n=6) or the vehicle (n=6) for 3 weeks. Histological analyses were performed in the retroperitoneal (rWAT) and inguinal (iWAT) WAT to determine adipocyte size and number. Specific markers for adipogenesis and WAT functionality were analysed in rWAT using quantitative RT-PCR.GSPE or gallic acid supplementation did not reduce weight gain or reverse and adiposity. However, GSPE reduced adipocyte size significantly in rWAT and moderately in iWAT and tripled the adipocyte number in rWAT. Gallic acid slightly reduced adipocyte size in rWAT and iWAT and doubled the adipocyte number in both WATs. In accordance with this adipogenic activity, Pref-1 and PPAR? tended to be overexpressed in rWAT of rats supplemented with GSPE. Moreover, GSPE supplementation increased Plin1 and Fabp4 expression and restored adiponectin expression completely, indicating a better functionality of visceral WAT.GSPE supplementation has anti-hypertrophic and hyperplasic activities in rats with established obesity, mainly in visceral WAT inducing a healthier expansion of WAT to match the surplus energy provided by the cafeteria diet.

Dataset Information

Inhibiting amyloid ?-protein assembly: Size-activity relationships among grape seed-derived polyphenols.

Publications

Inhibiting amyloid β-protein assembly: Size-activity relationships among grape seed-derived polyphenols.

Similar Datasets

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