Contained in the seeds of the grape is the power to …

Help Delay and Prevent Alzheimer’s
By whittling away amyloid-β neurotoxins that cause memory deficits.
By Will Block

Grape seed research is expanding.

T

here are a number of natural compounds that can serve to diminish the prospects of dementia, including its most rapacious form, the disease known as Alzheimer’s (DA), first identified 105 years ago by psychiatrist and neuropathologist Alois Alzheimer. Take, for instance, galantamine, omega-3 fatty acids, choline, vitamin B5, vitamin B12, vitamin E (especially the succinate form), vitamin C, folate, turmeric, lithium, green tea (especially ECGC), quercetin, resveratrol, BHT, cinnamon, melatonin, anti-AGE supplements [including vitamin B1 (as benfotiamine and as thiamine), vitamin B6, alpha-lipoic acid, carnosine, histidine, and rutin], and purple corn color.1 These are all variously beneficial. And now add grape seed extract to these Alzheimer’s nutrients.


† Up until now, I’ve followed suit with the literature and used the acronym AD (Alzheimer’s disease). But that has been far too positive a connotation (as if Alzheimer’s was an AD-dition rather than a subtraction of capabilities), and thus confusing. So in this article, I will reverse the letters and call it DA (disease of Alzheimer’s) as in “dah,” the retard intonation, which is more representative of the downward path taken by DA’s progression into the abyss of memory loss.


In a recent study, conducted at Mount Sinai School of Medicine in New York City, it has been found that grape seed extract—containing natural antioxidant polyphenols—is able to help delay or prevent the development or the progression of DA.2 Led by Giulio Maria Pasinetti, MD, PhD, the research effort was the first of its kind to evaluate the ability of grape-derived polyphenols to prevent the generation of a specific form of amyloid-β (Aβ) plaque in the mammalian brain. In partnership with a team at the University of Minnesota, Pasinetti and his collaborators administered grape seed polyphenolic extract (GSPE) to mice genetically bred to develop memory deficits and Aβ neurotoxins similar to those found in DA. They found that the brain content of a particular form of Aβ—Aβ*56, the name of which is based on the molecular weight of the Aβ structure—previously implicated in the promotion of Alzheimer’s disease memory loss, was substantially reduced after treatment.

Aβ plaque, in general, has long been thought to cause the neurotoxicity associated with DA. However, there is growing acceptance that oligomers—a form of plaque found in the brains of DA patients and mouse models of DA—cause the toxin destruction of synapses and consequential memory impairment that leads to DA. When plaque is oligomerized it becomes more soluble. Thus it more readily accumulates in the extracellular areas. These soluble high-molecular-weight Aβ oligomers are now increasingly thought to be chiefly responsible for DA dementia and memory deficits in a mouse model of DA, and by implication in the brains of humans with DA.

All Plaques Are Not Equally Bad

In previous studies, GSPE has been found to inhibit Aβ oligomerization in vitro.3,4 GSPE also has been shown to reduce cognitive impairment and DA-related neuropathology in the brains of DA-model mice. Subsequently, in the Mount Sinai study, GSPE was given to the same breed of mice for five months, during which time it significantly decreased brain levels of Aβ*56, an oligomerized form of plague. This soluble amyloid polymer has previously been shown to induce memory dysfunction in rodents, surprisingly without changing the levels of transgenic Aβ protein precursor, monomeric Aβ, or other Aβ oligomers.5


The research effort was
the first of its kind to evaluate the
ability of grape-derived polyphenols
to prevent the generation of perhaps
the most devastating form of
amyloid-β plaque.


This is contrary to the idea, frequently promoted in the popular press, that all amyloid plaque is equally bad. Indeed, Aβ protein exists in a variety of assembly states, including amyloid plaques and soluble Aβ oligomers. While both of these forms of Aβ have been shown to impair neuronal function, their roles in DA-associated memory loss are only now becoming clear. Complicating the issues, both amyloid plaques and soluble Aβ oligomers are often present in the brain at the same time. This has made it hard to evaluate the effects of plaques and oligomers separately on memory function.

The Wrong Type of Plaque

In the prior study cited, it was found that Aβ*56 can impair memory function in the absence of other types of amyloid plaques.5 Upon examination, DA-model mice that had plaques, but markedly reduced levels of Aβ oligomers, were found to have normal memory function. This finding supports the necessity of Aβ oligomers, such as Aβ*56, in memory loss. To repeat, these observations emphasize, at least initially, that amyloid plaques in general do not necessarily impair memory.

Returning to Pasinetti et al, the results provide the first clear demonstration that a natural, safe, and affordable supplement can reduce levels of a memory-impairing Aβ oligomer in vivo. Furthermore, for the first time, it is strongly suggested that GSPE should be further studied as both a potential preventative and/or therapeutic agent for DA. The amount of GSPE used in the DA-model mice was the equivalent of 1 g/day for an average weight human.

These conclusions are in keeping with previous studies hypothesizing that increased consumption of grape-derived polyphenols, whose content is fairly high in red wine, may protect against cognitive decline in Alzheimer’s. By showing a selective decrease in the neurotoxin Aβ*56 following grape-derived polyphenols treatment, the Mt. Sinai findings substantiate those theories.

Among other considerations for GSPE, it has been shown to reduce cognitive decline and neuropathology in DA-model mice, which are believed to model the pre-dementia phase of DA. Using an antibody that recognizes oligomers of various amyloidogenic proteins, it was shown that GSPE reduced the levels of oligomers in the brains of these animals.


Upon examination, DA-model mice
that had plaques, but markedly
reduced levels of Aβ oligomers,
were found to have
normal memory function.


The principal goal of the Mt. Sinai study was to determine whether GSPE modulated specific Aβ assemblies with demonstrated effects on memory function, and that was found to be true, with GSPE decreasing Aβ*56. Yet GSPE did not affect expression of full-length AβPP (Aβ precursor protein) in the model mice. So in order to assess the effects of GSPE on the activities of AβPP processing enzymes in the current study, levels of C-terminal cleavage products of a- and β-secretases were measured. It is significant that both enzyme activities appeared unaltered by GSPE treatment. This is consistent with previous results showing that GSPE treatment did not affect levels of soluble N-terminal AβPP cleavage products (sAβPPa and sAβPPβ). But it raises a question about the current finding that steady-state levels of soluble monomeric Aβ were unaffected by GSPE. This might appear inconsistent with previous findings that GSPE treatment led to a significant increase in Aβ monomer levels.

Solubility Makes the Difference

However, the earlier findings measured water-soluble total Aβ, while the current study measured Aβ in detergent-solubilized tissue. Soluble Aβ oligomers have been increasingly recognized as synaptotoxic agents that might trigger cognitive impairment in DA. Aβ*56 correlates with memory deficits in multiple lines of AβPP transgenic mice and is sufficient to cause memory dysfunction in normal, healthy rats.

In prior studies, a dimer-enriched brain extract and cerebrospinal fluid from DA patients were found to impair synaptic plasticity. But in the current study, GSPE led to a non-significant trend towards a decrease in soluble Aβ dimers. Detections of multimeric Aβ species, including dimeric and Aβ*56 species, by Pasinetti et al and other investigators depend on the use of antibodies capable of recognizing these multimeric Aβ species. Yet, there is no information confirming whether these antibodies display equal affinity toward dimeric Aβ, Aβ*56, and/or other Aβ species. Thus, in the current study, it is not possible to determine the relative proportion of Aβ dimer and Aβ*56 in relationship to total contents of multimeric Aβ species in the brain.


† A dimer is a chemical structure formed from two sub-units. It is an oligomer, a molecule that consists of a few monomer units (oligos, is Greek for “a few”), in contrast to a polymer that potentially may consists of an unlimited number of monomers. Trimers and tetramers are also oligomers.



The results provide the first clear
demonstration that a natural, safe,
and affordable supplement
can reduce levels of a memory-
impairing Ab oligomer in vivo.


Importantly, while Pasinetti et al have demonstrated that GSPE significantly modulated the contents of Aβ*56 and exhibited a trend of reduction of Aβ dimer, it would be extremely interesting to determine how GSPE might modulate the relative proportions of Aβ dimer and Aβ*56 in the brain. We’ll have to wait on their future research findings.

Negligible Adverse Events

According to Dr. Pasinetti, “Since naturally occurring polyphenols are also generally commercially available as nutritional supplements and have negligible adverse events even after prolonged periods of treatment, this new finding holds significant promise as a preventive method or treatment, and is being tested in translational studies in Alzheimer’s disease patients.”6

Notwithstanding their finding, the Mt. Sinai study authors underscore the need for scientists to identify a biomarker of DA that would pinpoint those who are at high risk to develop Alzheimer’s disease. That would make sense if there were no other benefits from GSPE, but other research has shown a wide spectrum of use.

GSPE Can Be Beneficial for Type 2 Diabetes

For example, at the Academic Unit of Diabetes and Endocrinology, Queen Alexandra Hospital in Portsmouth, UK, researchers hypothesized that many of the markers of type 2 diabetes such as vascular risk due to endothelial dysfunction, oxidative stress, inflammation, and insulin resistance could be addressed by GSPE.7

In their study, 32 type 2 diabetics (16 men and 16 women) who were prescribed diet or oral glucose-lowering agents also received GSPE (600 mg/day) or placebo for 4 weeks in a double-blinded randomized crossover trial. This study aimed to determine if GSPE could improve these markers in high-risk cardiovascular subjects with type 2 diabetes. At the baseline means, the age was 61.8 ± 6.36 years; the body mass index was 30.2 ± 5.92 kg/m2 (30 is the threshold for obesity); and the duration of the subject’s diabetes was 5.9 ± 2.14 years.


The amount of GSPE used in the
Alzheimer’s-model mice was the
equivalent of 1 g/day for
an average weight human.


Markers of endothelial function, oxidative stress, reduced glutathione/oxidized glutathione, inflammation (CRP), urinary albumin:creatinine ratio, insulin resistance and metabolism were measured at baseline and after intervention with GSPE or placebo.

Following GSPE (but not placebo), significant changes were noted in metabolism, whole blood glutathione, and CRP. At the same time, total cholesterol concentration was found to have decreased. No statistically significant changes were shown in endothelial function, insulin resistance, or oxidative stress. GSPE significantly improved markers of inflammation and glycemia. It also improved a single marker of oxidative stress. These results, in obese type 2 diabetic subjects at high risk of cardiovascular events over a 4-week period, strongly suggest that GSPE may have a therapeutic role in decreasing cardiovascular risk.

GSPE May Help Prevent Atherosclerosis

In Japan, a group of researchers from several corporations (including Kikkoman, the leading producer of soy sauce) and Wayo Women’s University in Chiba undertook a 12-week study of the effects of grape seed extract on two markers of human health, one negative and one positive.8 The study was randomized, placebo-controlled, and single-blind (double-blind is better).

The negative marker of health was oxidized LDL-cholesterol. The positive marker was adiponectin, a hormone-like protein produced in adipocytes (fat cells); its principal effect is to enhance insulin sensitivity in peripheral tissues. This reduces the risk for type 2 diabetes, which is essentially an extreme form of insulin resistance and which opens the door wide to other degenerative disorders, including atherosclerosis. Low levels of adiponectin have been associated with increased risks for obesity, diabetes, and atherosclerosis.

For their study, the researchers used 53 healthy men and women, average age 52, whose plasma LDL-cholesterol levels were between 100 and 180 mg/dL (milligrams per deciliter). According to the American Heart Association, LDL-cholesterol levels this high range from above optimal to very high. (It’s useful to remember, by the way, that LDL-cholesterol levels are considered to be a more accurate indicator of cardiovascular risk than the more commonly cited total cholesterol levels.


GSPE has been shown to reduce
cognitive decline and neuropathology
in Alzheimer’s-model mice which is
believed to model the pre-dementia
phase of Alzheimer’s disease.


Grape Seed Extract Inhibits Oxidation of LDL-Cholesterol

The GSPE used in the study contained 72% proanthocyanidins, by weight, and the amounts of extract used were calculated to deliver either 200 mg or 400 mg of these compounds daily. Compared with placebo, they had no effect on the blood levels of LDL-cholesterol per se, but they did produce a statistically significant reduction in the levels of oxidized LDL-cholesterol, with the higher dose showing the stronger effect (a 14% reduction).

There was no statistically significant effect, however, on adiponectin levels, nor were there any significant effects on total cholesterol, triglycerides, or any of a wide array of nonlipid components in the subjects’ blood. Neither were there any significant effects on body weight or blood pressure. As well, there were appreciable increases in HDL-cholesterol (the “good cholesterol”), but oddly, this was true in the placebo group too, and it turned out that there were no significant differences among the three groups in that regard.

An Abundance of Other Reasons

There are numerous other motives to consider GSPE, including its ability to decrease fat (see “Grape Seed Extract May Inhibit Fat Absorption” in the July 2007 issue), its ability to help maintain a weight-loss program (see “Supplements We Take with Our Meals to Enhance Health and Healthy Weight Management” in the May 2007 issue), and its ability to dissipate laminar shear stress, the frictional force exerted on the endothelial cells lining blood vessels by the flow of blood moving slowly enough that it doesn’t break up into chaotic, turbulent flow (see “Beneficial Effects of the Laminar Shear Stress Response Mimicked by Procyanidin-Rich Grape Seed Extract and Hawthorn” in the October 2006 issue).

The Choice Is Yours

Fig. 1. The amount of Aβ*56 in the forebrains of GSPE-treated mice was cut by about 50%.

LEM1109graph167x109.gif
Click on thumbnail
for full sized image

Returning to Dr. Pasinetti, “It will be critical to identify subjects who are at high risk of developing Alzheimer’s disease, so that we can initiate treatments very early and possibly even in asymptomatic patients. … However, initial stages of the disease, early intervention with this treatment might be beneficial as well. Our study implicating that these neurotoxins such as Aβ*56 in the brain are targeted by grape-derived polyphenols holds significant promise.” (See Figure 1.) Promises, promises … In Pasinetti’s prior quote he stated that GSPE has “negligible adverse events even after prolonged periods of treatment.” With no evidence of a downside, compared to a great upside, there is no reason not to add this extraordinary nutrient to your supplement program. Think delay and protection!

References

  1. Shih PH, Wu CH, Yeh CT, Yen GC. Protective effects of anthocyanins against amyloid β-peptide-induced damage in neuro-2A cells. J Agric Food Chem 2011 Mar 9;59(5):1683-9.
  2. Liu P, Kemper LJ, Wang J, Zahs KR, Ashe KH, Pasinetti GM. Grape seed polyphenolic extract specifically decreases Aβ*56 in the brains of Tg2576 mice. J Alzheimers Dis 2011 Jul 8. [Epub ahead of print]
  3. Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, Humala N, Teplow DB, Pasinetti GM. Grape-derived polyphenolics prevent Abeta oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. J Neurosci 2008 Jun 18;28(25):6388-92.
  4. Ono K, Condron MM, Ho L, Wang J, Zhao W, Pasinetti GM, Teplow DB.Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem 2008 Nov 21;283(47):32176-87.
  5. Lesné S, Kotilinek L, Ashe KH. Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 2008 Feb 6;151(3):745-9.
  6. The Mount Sinai Hospital/Mount Sinai School of Medicine (2011, July 18). Natural chemical found in grapes may protect against Alzheimer’s disease. ScienceDaily. Retrieved July 20, 2011, from http://www.sciencedaily.com/releases/2011/07/110715135211.htm
  7. Kar P, Laight D, Rooprai HK, Shaw KM, Cummings M. Effects of grape seed extract in Type 2 diabetic subjects at high cardiovascular risk: a double blind randomized placebo controlled trial examining metabolic markers, vascular tone, inflammation, oxidative stress and insulin sensitivity. Diabet Med 2009 May;26(5):526-31.
  8. Sano A, Uchida R, Saito M, Shioya N, Komori Y, Tho Y, Hashizume N. Beneficial effects of grape seed extract on malondialdehyde-modified LDL. J Nutr Sci Vitaminol 2007;53:174-82.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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