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. 2009;16(1):59-72.
doi: 10.3233/JAD-2009-0916.

Heterogeneity in red wine polyphenolic contents differentially influences Alzheimer's disease-type neuropathology and cognitive deterioration

Lap Ho  1 , Ling Hong Chen, Jun Wang, Wei Zhao, Stephen T Talcott, Kenjiro Ono, David Teplow, Nelson Humala, Alice Cheng, Susan S Percival, Mario Ferruzzi, Elsa Janle, Dara L Dickstein, Giulio Maria Pasinetti
Affiliations

Heterogeneity in red wine polyphenolic contents differentially influences Alzheimer's disease-type neuropathology and cognitive deterioration

Lap Ho et al. J Alzheimers Dis. 2009.

Abstract

We recently found that moderate consumption of two unrelated red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer's disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-beta (Abeta) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Abeta neuropathology and Abeta-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Abeta molecules to soluble high-molecular-weight Abeta oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Abeta-related mechanisms. Results from these studies suggest the possibility of developing a "combination" of dietary polyphenolic compounds for AD prevention and/or therapy by modulating multiple Abeta-related mechanisms.

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Figures

Fig. 1a
Fig. 1a
Chemical analysis of Cabernet Sauvignon and muscadine wines. Constituent polyphenolic components in Cabernet Sauvignon (A,C,E) and muscadine (B,D,F) wines were analyzed by reverse phase HPLC using a C18 column. (A,B) Detection of phenolic acid compounds at 280 nm. (C,D) Detection of flavonoids at 370 nm. (E,F) Detection of anthocyanins at 520 nm. (G) Identification of polyphenols corresponding to peaks detected in panel (A-F) based on spectroscopic interpretations
Fig. 1b
Fig. 1b
Chemical analysis of Cabernet Sauvignon and muscadine wines. Constituent polyphenolic components in Cabernet Sauvignon (A,C,E) and muscadine (B,D,F) wines were analyzed by reverse phase HPLC using a C18 column. (A,B) Detection of phenolic acid compounds at 280 nm. (C,D) Detection of flavonoids at 370 nm. (E,F) Detection of anthocyanins at 520 nm. (G) Identification of polyphenols corresponding to peaks detected in panel (A-F) based on spectroscopic interpretations
Fig. 2
Fig. 2
Muscadine treatment improves spatial memory function in Tg2576 mice. Assessments of spatial memory behavioral functions of 14 month old muscadine-treated (Tg-muscadine) and control, gender- and age-matched non-treated (Tg-control) Tg2576 mice using the Morris water maze (MWM) protocol. (A) Learning trial hidden-platform acquisition curves. Tg-muscadine group performed significantly better than the control, non-treated group (Tg-control) [2-way ANOVA analysis of Tg-muscadine vs. Tg-control groups for muscadine treatment (p < 0.05, F = 4.24, DFn = 1, DFd = 84) and for training days (p < 0.05, F = 6.43, DFn = 6, Dfd = 84)]. (B) Probe trial conducted 24 hours after completion of hidden-platform training. Muscadine-treated Tg2576 mice exhibited a significantly higher preference for the target platform compared to control, non-treated Tg2576 mice (p < 0.05, 2-tailed Student t test). (C) Visible-platform learning curves. There is no significant difference in visible platform performance among Tg-muscadine compared to Tg-control mice. (D) Average swimming speed. There is no significant difference in swimming ability of muscadine-treated animals compared to control, non-treated animals. In (A-D) Values represent group mean (+SEM); n = 7–9 mice per group.
Fig. 3
Fig. 3
Muscadine treatment significantly reduced Aβ neuropathology in Tg2576 mice. Tg2576 mice were assessed for indexes of AD-type amyloid burden in the brain in response to muscadine treatment using stereological technologies; the same 14 month old Tg2576 mice used for behavioral assessments in Fig. 2 were used in this study. (A) Assessments of amyloid neuritic plaque density in cerebral cortex and in the hippocampal formation of brain specimens from muscadine-treated and control, non-treated Tg2576 mice. (A, inset) Control studies confirming muscadine treatment did not modulate expression of the holo-AβPP in the brain (cerebral cortex). Bar graphs represent means ± SEM., n = 6–8 per group; * P < 0.05 vs. non-treated control Tg2576 group (2-tailed Student's t test). (B) Representative micrograph of brain specimen stained for amyloid neuritic plaques in muscadine-treated (Tg-musc.) or in control, non-treated (Tg-cont.) Tg2576 mice.
Fig. 4
Fig. 4
No detectable changes in α-, β- and γ-secretase activities in the brain of Tg2576 mice in response to muscadine treatment. α–, β-, and γ-secretase enzymatic activities were assessed in cerebral cortex brain specimens from the same 14 month old Tg2576 animals used in the behavioral studies in Fig. 2 and neuropathology assessments in Fig. 3. (A) α-secretase activity, (B) β-secretase activity, and (C) γ-secretase activity in Tg-muscadine and Tg-control mice. (A-C). Bar graphs represent group mean (± SEM), n = 6–8 per group.
Fig. 5
Fig. 5
Muscadine treatment significantly attenuated the accumulation soluble HMW Aβ species in the brain of Tg2576 mice. The contents of HMW Aβ oligomeric species in cerebral cortex brain specimens from muscadine-treated or control, non-treated 14 month old Tg2576 mice were assessed by independent dot-blot (A) and western blot studies (B). (A) Immunodetection of HMW Aβ oligomeric species in the cerebral cortex and in the hippocampal formation using the oligomer-specific antibody A11 antibody in an dot blot assay. (A, inset) Representative A11-immunoreactive dot-blot analysis of cortical and hippocampal formation brain specimens. Abbreviations: C: control, non-treated Tg2576 mice; M: muscadine-treated Tg2576 mice. (B) Western blot analysis in which HMW Aβ oligomeric species are resolved by gel electrophoresis followed by immunodetection using a pan-Aβ 6E10 antibody. (B, Inset) Representative western blot analysis of muscadine-treated and control non-treated Tg2576 mice. Immunoreactive holo-AβPP and relatively less abundant HMW Aβ species are identified. In (A, B), bar graphs represent means ± SEM., n = 6–8 per group; * P < 0.05 vs. non-treated control Tg2576 group (2-tailed Student's t test).
Fig. 6
Fig. 6
Muscadine polyphenols exert anti-Aβ oligomerization bioactivity in vitro. (A) Muscadine wine interferes with aggregation of synthetic Aβ1–42 peptides into HMW oligomer Aβ species, in vitro. Synthetic Aβ1–42 peptides were aggregated in the absence or in the presence of muscadine wine. Aβ species were then resolved by molecular size, transblotted onto a nitrocellulose membrane, followed by immunodetection of Aβ peptides using and the 6E10 antibody. Lane 1 represents non-aggregated Aβ1–42 peptides; Lane 2, aggregated Aβ1–42 peptides; Lane 3, Aβ1–42 peptides aggregated in the presence of 1.2% ethanol (the same amount of ethanol presented in the aggregation assay in the presence of muscadine in Lane 4); Lane 4, Aβ1–42 peptides aggregated in the presence of 1 μl muscadine wine. (B) Application of an independent PICUP assay to explore the role of muscadine wine and its polyphenolic components to interfere with aggregations of synthetic Aβ1–40 peptides. The PICUP assay is designed to explore the initial protein-protein interactions that are necessary for the formation of HMW Aβ oligomeric species. Aβ aggregates are stabilized by photo-cross-linking. Monomeric and multimeric Aβ species are separated by molecular size and visualized by silver staining. Lane 1 represents molecular weight marker; Lane 2, non-aggregated Aβ1–40 peptide; Lane 3, aggregated Aβ1–40 peptide; Lane 4, Aβ1–40 peptide aggregated in the presence of muscadine wine (2 μl of the wine); Lane 5, Aβ1–40 peptide aggregated in the presence of a polyphenolic extract from 2 μl of the muscadine wine. The position of Aβ1–40 monomer, dimmer, trimer and 4-mer are as indicated.
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References

    1. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-[beta] protein specifically disrupt cognitive function. Nat Neurosci. 2005;8:79–84. - PubMed
    1. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006;440:352–357. - PubMed
    1. Jacobsen JS, Wu CC, Redwine JM, Comery TA, Arias R, Bowlby M, Martone R, Morrison JH, Pangalos MN, Reinhart PH, Bloom FE. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 103:5161–5166. - PMC - PubMed
    1. Cummings BJ, Cotman CW. Image-analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity. Lancet. 1995;346:1524–1528. - PubMed
    1. Luchsinger JA, Tang MX, Siddiqui M, Shea S, Mayeux R. Alcohol intake and risk of dementia. J Am Geriatr Soc. 2004;52:540–546. - PubMed

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