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Recent studies suggest that moderate red wine consumption reduces the incidence of Alzheimer's disease (AD) clinical dementia. Using Tg2576 mice, which model AD-type amyloid beta-protein (Abeta) neuropathology, we tested whether moderate consumption of the red wine Cabernet Sauvignon modulates AD-type neuropathology and cognitive deterioration. The wine used in the study was generated using Cabernet Sauvignon grapes from Fresno, California, and was delivered to Tg2576 in a final concentration of approximately 6% ethanol. We found that Cabernet Sauvignon significantly attenuated AD-type deterioration of spatial memory function and Abeta neuropathology in Tg2576 mice relative to control Tg2576 mice that were treated with either a comparable amount of ethanol or water alone. Chemical analysis showed the Cabernet Sauvignon used in this study contains a very low content of resveratrol (0.2 mg/L), 10-fold lower than the minimal effective concentration shown to promote Abeta clearance in vitro. Our studies suggest Cabernet Sauvignon exerts a beneficial effect by promoting nonamyloidogenic processing of amyloid precursor protein, which ultimately prevents the generation of Abeta peptides. This study supports epidemiological evidence indicating that moderate wine consumption, within the range recommended by the FDA dietary guidelines of one drink per day for women and two for men, may help reduce the relative risk for AD clinical dementia.

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Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease-modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O-glucuronide, significantly reduced the generation of β-amyloid (Aβ) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Aβ generation. Moreover, in an in vitro analysis using the photo-induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein-protein interaction of Aβ(1-40) and Aβ(1-42) that is necessary for the formation of neurotoxic oligomeric Aβ species. Lastly, we found that quercetin-3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD.

Little information is available regarding possible synergistic or antagonistic biochemical interactions among polyphenols contained in fruits and vegetables. Identifying potential interactions among these compounds may help to define the efficiency of polyphenol-containing foods in cancer prevention as related to structure-function activity of the compounds. The objective of this study was to investigate interactions between quercetin and ellagic acid, two polyphenolics that are present predominantly in small fruits, on cell death and proliferation-related variables in the MOLT-4 human leukemia cell line. Assays were performed to determine cell cycle kinetics, proliferation, apoptotic DNA-fragmentation and caspase-3-activity after 12, 24 and 48 h. Ellagic acid significantly potentiated the effects of quercetin (at 5 and 10 micro mol/L each) in the reduction of proliferation and viability and the induction of apoptosis. Significant alterations in cell cycle kinetics were also observed. The synergy was confirmed by an isobolographic analysis of the cell proliferation data. The interaction of ellagic acid and quercetin demonstrated an enhanced anticarcinogenic potential of polyphenol combinations, which was not based solely on the additive effect of individual compounds, but rather on synergistic biochemical interactions.