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,,1
* Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA;
Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA,
Geriatric Research and Clinical Center, James J. Peters VA Medical Center, Bronx, New York, USA; and
Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida, USA
1Correspondence: Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Pl., New York, NY 10029, USA. E-mail: giulio.pasinetti{at}mssm.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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6% ethanol. We found that Cabernet Sauvignon significantly attenuated AD-type deterioration of spatial memory function and Aß 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 Aß 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 Aß 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.—Wang, J., Ho, L., Zhao, Z., Seror, I., Humala, N., Dickstein, D. L., Meenakshisundaram, T., Percival, S. S., Talcott, S. T., Pasinetti, G. M. Moderate consumption of Cabernet Sauvignon attenuates Aß neuropathology in a mouse model of Alzheimer’s disease.
Key Words: APP • nonamyloidogenic • polyphenols • AD dementia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3
4
5)
. The mechanism by which red wine may influence AD is unknown. However, recent evidence implicates that polyphenols, which are present in red wine, fruits, vegetables, and other food products, can inhibit aggregation of synthetic Aß peptides in vitro (6
, 7)
. It is currently unknown whether red wine intake in moderate doses can beneficially influence AD-related dementia.
AD is a growing public health concern with potentially devastating effects. There is presently no cure for or means of preventing AD. While genetic factors contribute to early-onset AD, they play less of a role in late-onset, sporadic AD, which is the most common form (8)
. Most important, life style factors such as diet (9
10
11)
, environmental enrichment (9
, 10
, 12)
, and exercise (13)
are receiving increasing attention for their potential preventive and therapeutic impact on AD.
In this study, we report that moderate consumption of Cabernet Sauvignon delivered in drinking water for 7 months significantly reduces AD-type Aß neuropathology and attenuates spatial memory decline in 11-month-old Tg2576 mice.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cabernet Sauvignon and polyphenolic extraction
Cabernet Sauvignon was generated from Vitis vinifera at the University of Florida as described previously (14)
. Cabernet Sauvignon grapes from Fresno, California, were shipped to Gainesville by air freight; grapes were crushed, destemmed, and allowed to ferment on the skins for 7 days at 13°C. The must was pressed and allowed to finish fermenting to dryness (>0.05% reducing sugar) at 13°C. Wines were then treated with 100 mg/L of potassium metabisulfite, cold-stabilized at 3°C for 2 months, filtered, and stored at 13°C for 14 months. The composition of Cabernet Sauvignon was assessed using the Waters 2695 HPLC system with a Waters Spherisorb Octadecyl silane column (4.6x250 mm) and the solvent conditions of Talcott and Lee (15)
; peaks were identified based on spectral characteristics. Polyphenols were quantified against authentic standards, when available; flavonoids were quantified in quercetin equivalents (Fig. 1
). Our Cabernet Sauvignon contained 12% alcohol, as determined by ebulliometry (16)
, and had a titratable acidity (as tartaric acid) of 6 g/L and a pH of 3.6. For in vitro studies, polyphenol extract was prepared by extracting the Cabernet Sauvignon using acetonitrile-butanol (1:1, v/v), followed by vacuum centrifugation, to concentrate the extracted polyphenol compounds and remove volatile organic components, including ethanol from the wine as well as organic solvents used in the extraction. HPLC analysis confirmed that the contents of polyphenol components in the extract were comparable to Cabernet Sauvignon (data not shown).
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Behavioral assessment of cognitive functions by Barnes maze test
Spatial learning memory was assessed by the Barnes’ maze behavioral test as described previously (17)
. Briefly, at 10 months of age mice were placed on a white circular platform (69 cm in diameter) with 16 equally spaced concentric holes at the periphery. In this assay, spatial memory is assessed by recording the latency time for the animal to escape from the platform into an escape box as a function of learning trials during the learning phase. Three days after the learning phase, mice are examined in a reversal phase test by switching the escape box to 180 degrees without changing the visual cue. Wine or ethanol solution was removed 3 days before behavioral assessment and mice were alcohol free for the duration of the testing period.
Assessment of AD-type amyloid neuropathology
For quantitative assessment of brain Aß peptides, frozen pulverized tissue was homogenized in 5 mol/L guanidine buffer, diluted 1:10 in PBS containing 0.05% (v/v) Tween-20 and 1 mmol/L Pefabloc protease inhibitors (Roche Biochemicals, Indianapolis, IN, USA), and centrifuged for 20 min at 4°C. Total Aß1–40 or Aß1–42 was quantified by sandwich ELISA (BioSource, Camarillo, CA, USA), as described previously (10
, 11)
. For stereologic assessment of AD-type amyloid burden in Tg2576 mice, freshly harvested brain hemispheres were immersion-fixed overnight in 4% paraformaldehyde and sectioned in the coronal plane on a vibratome at a nominal thickness of 50 µm. Every 15th section was selected from a random start position and processed for thioflavine-S staining (18)
. All stereologic analyses were performed using a Zeiss Axiophot photomicroscope equipped with a Zeiss motorized stage and MSP65 stage controller, a high-resolution Zeiss ZVS-47E digital camera, and a Macintosh G3 computer running the custom-designed software NeuroZoom (19)
. The amyloid burden was estimated using the Cavalieri principle with a small-sized grid (50x50 µm) for point counting (20)
; this procedure provides an unbiased estimate of the fractional volume occupied by amyloid plaques expressed as a percentage of the neocortical or hippocampal volume. Estimates of plaque volume were obtained using a systematic random sampling procedure at x40 magnification.
Cell cultures and treatments with Cabernet Sauvignon polyphenolic extract
Embryonic day 15 cortico-hippocampal neuronal cultures were prepared from heterozygous Tg2576 transgenic mice (Tg2576 neurons) (21)
. Embryonic brain tissue was mechanically triturated and centrifuged. Neurons were seeded onto poly-D-lysine-coated 24-well plates at 5 x 105 cells per well and cultured in serum-free, chemically defined medium Neurobasal supplemented with 2% B27, 0.5 mM L-glutamine, and 1% penicillin-streptomycin (Gibco-BRL, Carlsbad, CA, USA). The absence of astrocytes (<2%) was confirmed by the virtual absence of glial fibrillary acidic protein immunostaining (data not shown). Aliquots of the Cabernet Sauvignon used for in vivo studies were extracted in acetonitrile:butanol (1:1, v/v), dried under vacuum centrifugation, and used for treatment in Tg2576 neuronal cultures. Polyphenolic extracts stored at 4°C were reconstituted to their original volume in culture medium, then added to cultures as fresh medium. After treatment, conditioned medium was collected for Aß detection. Cell viability was assessed by LDH assay using commercial available kit (Promega, Madison, WI, USA).
Secretase activity assays and assessment of carboxyl-terminal fragments (CTF) processing of amyloid precursor protein (APP)
-, ß-, and 
-Secretase activities were assessed using commercially available kits (R&D Systems, Minneapolis, MN, USA) (10
, 11)
. Brain samples (neocortex) or primary Tg2576 neuron cultures were homogenized in supplied buffers. Homogenate was then added to secretase-specific APP peptide conjugated to the reporter molecules EDANS and DABCYL. In the uncleaved form, fluorescent emissions from EDANS are quenched by the physical proximity of the DABCYL moiety, which exhibits maximal absorption at the same wavelength (495 nm). Cleavage of APP peptide by secretase physically separates the EDANS and DABCYL reporter molecules, allowing for the release of a fluorescent signal. The level of secretase enzymatic activity is proportional to the fluorometric reaction in the homogenate (R&D Systems).
-, ß-, and -CTFs in the brain samples (neocortex) were assessed as described with modifications (22)
. Frozen pulverized brain samples were homogenized in 9 volumes (w/v) of buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% SDS, 5 mM EDTA, 2 mM 1,10-phenanthroline, and Sigma protease inhibitor mixture), boiled, sonicated, boiled again, and centrifuged at 16,000 g. Supernatant was diluted 10-fold with 50 mM Tris-HCl, and CTF fragments were immunoprecipitated with antibody (Ab) C8 (raised against AA 676–695 of human APP cytoplasmic domain; gift of Dr. Dennis Selkoe, Brigham and Women’s Hospital) bound to protein A Sepharose beads (Roche Biochemicals, Indianapolis, IN, USA). After washing, SDS sample buffer was added and the samples were boiled, run on 10 to 20% Tris-Tricine gels (Bio-Rad Laboratories, Hercules, CA, USA), and transferred to nitrocellulose membranes. Membranes were boiled in PBS and blotted with Ab 369 raised against the cytoplasmic domain of APP. Immunoreactivity was visualized by fluorescence autoradiography using enhanced chemiluminescence (ECL) detection (SuperSignal Chemiluminescent Detection Kit; Pierce, Rockford, IL, USA) and quantified densitometrically.
Generation of CTF in membrane fractions of Tg2576 neurons was assessed as described by Sastre et al. (23)
with minor modifications. Cultured neuronal cells were washed twice with PBS, collected by centrifugation at 1500 g for 10 min, resuspended in homogenization buffer (10 mM MOPS, pH 7, 10 mM KCl, 1x complete protease inhibitor), and lysed by passing through a 26-gauge needle. Cell debris was removed by centrifugation at 2500 g at 4°C for 15 min. Membrane fractions were collected by centrifugation at 14000 g for 30 min, washed with homogenization buffer, then resuspended in assay buffer (150 mM Na-citrate, pH 6.4). Membrane fractions were incubated at 37°C for 2 h, and CTF fragments resolved on 10–20% Tris-Tricine gels were transferred to nitrocellulose membranes. Membranes were blotted with Ab C8. Immunoreactivity was visualized using ECL detection, the SuperSignal Chemiluminescent Detection Kit and quantified densitometrically. Full-length APP, sAPP, sAPPß were assessed as described (10)
.
Assessment of wine toxicity
Blood was collected after sacrifice by cardio puncture. Serum was collected by clotting for 10 min at room temperature and centrifugation at 2500 g for 20 min at 4°C. Serum was immediately subjected to total bilirubin, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) analysis using commercial enzyme assays according to the manufacturer’s instructions (Stanbio Laboratory, Boerne, TX, USA). Serum alcohol content was assessed using a commercial available kit (BioAssay Systems, Hayward, CA, USA).
Statistical analysis
All values are expressed as mean and SE. Differences between means were analyzed using either 2-way repeated measures ANOVA or 2-tailed Student’s t test. In all analyses, the null hypothesis was rejected at the 0.05 level. All statistical analyses were performed using the Prism Stat program (GraphPad Software, Inc., San Diego, CA, USA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A). The same protocol was also well tolerated by strain-, age-, and gender-matched WT mice (data not shown).
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Since each mouse consumed 4 ml of wine-adulterated water per day, we calculated that 7% of the total daily energy consumption in Cabernet Sauvignon-treated Tg2576 mice was derived from wine; this is equivalent to moderate human consumption. Five ounces (150 ml) of red wine is 6.2% of total energyintake for a woman (one 5-oz glass in a total of 2000 kcal/day) and 10% intake for a man (two 5-oz glasses in 2500 kcal per day) (Dietary Guidelines for Americans, 2005). We also calculated the amount of human wine consumption equivalent to mice drinking 4 ml of wine-adulterated water per day using FDA recommended criterion that takes into consideration body surface area: [human equivalent dose in mg/kg=animal dose in mg/kg x (animal wt in kg/human wt in kg)0.33] (U.S. Food and Drug Administration, 2005). We calculated that Cabernet Sauvignon-treated mice consumed 8 g of alcohol/kg body wt/day. This is equivalent to a human daily intake of 39.5 g alcohol per day, or daily consumption of 2.3 five-oz glasses (329.2 ml) of Cabernet Sauvignon. Thus, based on two independent calculations, we determined that mice in our study consumed an amount of Cabernet Sauvignon considered moderate by the U.S. Department of Agriculture and Health and Human Services. In control studies, 7 months consumption of Cabernet Sauvignon or ethanol resulted in a moderate content of blood ethanol (0.0298±0.0159% for Cabernet group and 0.0370±0.0243% for ethanol group vs. 0.0023±0.030% for water control group) in 11-month-old mice (Fig. 2B
). Most importantly, in parallel studies we found normal liver functions in the Cabernet Sauvignon and ethanol groups, as reflected by normal serum levels of bilirubin, alanine AST, and ALT (Fig. 2C
).
Moderate consumption of Cabernet Sauvignon attenuates AD-type cognitive deterioration in Tg2576 mice
Using the Barnes’ maze, we found that moderate consumption of Cabernet Sauvignon for 7 months significantly attenuated the decline in spatial memory activities in 11-month-old Tg2576 mice relative to controls, as reflected by a shorter latency to escape the Barnes’ maze platform as a function of learning trials during the learning phase (Fig. 3
A) (Cabernet Sauvignon group vs. water-only, 2-way ANOVA, P<0.0001 for wine treatment, P<0.4379 for escape latency over learning trials; Cabernet Sauvignon vs. ethanol group, P<0.04 for wine treatment, P<0.2084 for escape latency over learning trials). On the other hand, no significant difference in latency time during learning trials was found between ethanol and water-only groups (Fig. 3A
), suggesting that ethanol, at concentrations comparable to Cabernet Sauvignon treatment, does not significantly influence spatial memory in Tg2576 mice (ethanol vs. water only group, 2-way ANOVA, P<0.8 for ethanol treatment, P<0.2084 for escape latency over learning trials).
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In further control studies we found that moderate consumption of Cabernet Sauvignon in strain-, age-, and gender-matched WT mice did not influence spatial memory compared with either ethanol- or water-only WT mice (data not shown). This suggests that Cabernet Sauvignon attenuates AD-type spatial memory deterioration by modulating AD amyloid neuropathology in the brains of Tg2576 mice.
Even when the escape box was relocated 180° from its original position in the reversal learning trials, the performance of the Cabernet Sauvignon group continued to improve (Fig. 3B
). This rapid reversal learning phenomenon has been described in both the Barnes’ maze and the Morris water maze behavioral assessments for animals that successfully learned how to use the visual cues to improve on and optimize performance during the learning trials (17
, 24)
Consistent with their poor performance during the learning trials, ethanol and water-only controls also performed poorly in the reverse learning trials. Thus, Cabernet Sauvignon-treated Tg2576 mice had significantly shorter overall escape latency times in both learning and reverse learning trials compared with either ethanol or water-only mice, demonstrating that the Cabernet Sauvignon treatment attenuated spatial memory function deterioration in this AD mouse model.
Cabernet Sauvignon treatment prevents AD-type neuropathology in Tg2576 mice
We found that moderate consumption of Cabernet Sauvignon for 7 months, in addition to attenuating AD-type spatial memory functions in 11-month-old Tg2576 mice, also reduced amyloidogenic Aß1–40 and Aß1–42 peptides in the neocortex (P<0.05) and hippocampus (P<0.05) of the same mice compared with ethanol controls (Fig. 3C
). Consistent with this finding, Cabernet Sauvignon treatment compared with ethanol controls also decreased neocortical AD-type amyloid plaque burden (Fig. 3D
).
In control studies, we found that the neocortical concentration of Aß1–40 and Aß1–42 peptides or AD-type amyloid plaque burden did not differ significantly between ethanol and water-only groups (Fig. 4
A, B). Although there is a trend to reduction of Aß1–40 and Aß1–42 peptides in the ethanol-treated group, these changes are not statistically significant. Thus, we conclude that ethanol appears not to affect AD-type neuropathology in Tg2576 mice.
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Cabernet Sauvignon promotes nonamyloidogenic processing of APP in the brain of Tg2576 mice
To identify the mechanism by which Cabernet Sauvignon prevents AD-type amyloid neuropathology, we examined the impact of wine consumption on APP processing and Aß peptide generation. Aß species with different carboxyl termini are generated from APP through sequential proteolysis by ß- and -secretase; this amyloidogenic processing pathway results in the generation of membrane-bound ß- and -carboxyl terminal fragments (CTF) of APP. In the nonamyloidogenic pathway, APP is cleaved within the Aß domain by an -secretase to generate the -CTF of APP, thereby precluding generation (and deposition) of intact amyloidogenic Aß peptides in the brain (25)
Western blot assay revealed that moderate consumption of Cabernet Sauvignon elevated (P<0.05) concentrations of membrane-bound (C8-immunoreactive) -CTF cleaved fragment in the neocortex compared with ethanol-treated controls (Fig. 3E
). In addition, -secretase activity, assessed fluorometrically, was elevated in the brain of Cabernet Sauvignon-treated compared with ethanol-treated control Tg2576 mice (Fig. 3E
). On the other hand, there was no significant change in the neocortical concentration of ß- or -CTF (C8-immunoreactive), or in ß- or -secretase activity (Fig. 3E
). Thus, the Cabernet Sauvignon treatment seems to elicit a selective activation of the nonamyloidogenic processing of APP.
Not unexpectedly, the increase in -secretase activity was accompanied by an increase in neocortical concentration of soluble N-terminal (6E10-immunopositive) fragment of APP (sAPP) (Fig. 3F
), relative to ethanol controls. Moreover, in the control study we found that moderate consumption of Cabernet Sauvignon did not alter expression of the full-length holo-APP, nor did we observe any change in sAPPß (Fig. 3F
)
Cabernet Sauvignon polyphenolic extracts prevent Aß peptide generation coincidental with promotion of nonamyloidogenic processing of APP by -secretase activity in vitro
Since moderate Cabernet Sauvignon consumption significantly prevented AD-type amyloid neuropathology and cognitive deterioration in Tg2576 mice, we proceeded to investigate pharmacologically the potential application of Cabernet Sauvignon polyphenolic extract as novel therapeutics for AD. Cortico-hippocampal neuron cultures derived from embryonic day 15 (E15) Tg2576 mice were treated with Cabernet Sauvignon extract (50 and 100 µg/ml) and the conditioned medium was collected after 16 h. The polyphenolic extract significantly decreased the concentrations of Aß1–40 and Aß1–42 peptides in a dose-dependent manner, relative to vehicle-treated cultures, without exhibiting any cytotoxicity effect as evaluated by LDH release assay (data not shown). (Fig. 5
A)
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In addition, treatment of the cultures with 100 µg/ml of the polyphenolic extract significantly promoted -, but not ß- or -, secretase cleavage activity (Fig. 5B
), resulting in elevation of membrane-bound - but not -CTF (C8-immunoreactive in Western blots), relative to vehicle-treated cultures (Fig. 5B
); compared with the clear -CTF signal, ß-CTF was at the limit of detection preventing (reliable) quantification (Fig. 5B
). In addition to the selective elevation in membrane-bound -CTF, the concentration of sAPP in the conditioned medium was also increased without changes in holo-APP (Fig. 5C
) or sAPPß (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-secretase-mediated APP processing, thereby preventing or delaying the generation of amyloidogenic Aß peptide-associated cognitive deterioration. In primary neuron cultures derived from Tg2576 embryos, we found that Cabernet Sauvignon polyphenols exhibited Aß-lowering activity through promotion of nonamyloidogenic processing of APP.
Recent prospective studies showed that the relative risk of dementia was much lower in people who drank moderate amounts of red wine each day compared with total abstainers (2)
. The health benefits of wine have been ascribed in part to their polyphenol content (26)
. There is, however, no direct experimental evidence that red wine (or wine polyphenols) beneficially influence AD. The red wine, Cabernet Sauvignon, used in this study contains a wide variety of polyphenol compounds, including phenolic acids, flavonoids, and anthocyanins; most of the flavonoids and anthocyanins are in a glycosidic form (27)
. Some of the polyphenols contained in the Cabernet Sauvignon used in these studies were shown in vitro to attenuate the extension and eventually destabilize the polymerization of amyloidogenic Aß peptides (7)
. Accumulating evidence suggests that a specific polyphenolic compound, resveratrol, found in varying concentrations in red wine and many food products, may enhance Aß clearance by promoting intracellular proteosome activity in vitro (28)
. However, the role of resveratrol in our study is not clear since the Cabernet Sauvignon used in this study contains very low contents of this compound (0.2 mg/L, Fig. 1
), which is 10-fold lower than the minimal effective concentration shown to promote Aß clearance in vitro (28)
. Our studies suggest an alternative mechanism by which moderate consumption of polyphenols (red wine) exerts a beneficial effect by promoting nonamyloidogenic processing of APP, which ultimately prevents the generation of Aß peptides.
In view of the fact that accumulation of Aß peptides in the brain is a central feature of AD pathogenesis (29
, 30)
and is strongly suspected of contributing to cognitive deterioration (8)
, our data support the epidemiological evidence that moderate consumption of red wine may reduce the risk for AD. However, any purported health benefits of red wine must be weighed against the risk of dependence as well as contraindications such as preexisting heart, liver, and blood pressure conditions (31)
. In addition, wine provides nonnutrient-dense calories that may be contributing to obesity in an increasing number of our population. Nonetheless, after making these and other considerations on a case-by-case basis, the U.S. Department of Health and Human Services presently supports the promotion of moderate alcohol consumption in its national health promotion and disease prevention initiative, Healthy People 2010. This initiative states that "dietetics professionals may promote healthy lifestyles by reassuring the public that light to moderate alcohol consumption may have beneficial health outcomes for those who choose to drink, while heavy alcohol consumption is deleterious to health" (32)
. Thus, our preclinical data showing that moderate consumption of red wine in the form of Cabernet Sauvignon attenuates cognitive deterioration and Aß neuropathology in a mouse model of AD provide further support for this aspect of the Healthy People 2010 initiative, and suggest that moderation consumption of red wine might indeed promote AD prevention, as found for cardiovascular disorders (26
, 33
, 34)
.
Our study is the first to demonstrate a beneficial role of moderate red wine consumption in AD-type neuropathology and cognitive impairment. These data provide a strong impetus to ascertain the validity of the beneficial role of red wine and its polyphenol extracts in preclinical and clinical AD.
Received for publication April 5, 2006. Accepted for publication June 6, 2006.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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