Grape-derived Polyphenols Fight Amyloid, Head to Clinic

Polyphenols, plant compounds found in abundance in red wine and green tea, fight Aβ aggregation (see ARF related news story and Porat et al., 2006), a finding which has only served to further pique interest in the purported salubrious effects of these beverages. Indeed, experiments with transgenic mice engineered to overexpress a mutated human amyloid precursor protein indicate that a little Cabernet Sauvignon alongside their chow lessens amyloid build-up in brain (Wang et al., 2006). Following up on that study, the same group, led by Giulio Pasinetti at the Mount Sinai School of Medicine in New York, has a new paper in the June 18 issue of the Journal of Neuroscience showing that a commercially available polyphenol-rich grape seed extract inhibits Aβ oligomerization in vitro and reduces soluble Aβ oligomers and cognitive decline in the Tg2756 mouse model of AD. The results pave the way for testing of the extract in clinical trials for the prevention or treatment of AD.

The preparation, a water-soluble extract of grape seeds, is produced by a nutraceutical company by standardized procedures and contains greater than 90 percent total polyphenols, in the form of catechin and epicatechin. In the new work, the researchers, led by first author Jun Wang, show that the extract dose-dependently inhibits Aβ oligomerization in vitro, blocking the formation of soluble Aβ oligomers.

To test the in vivo activity of the extract, the investigators chose a fairly conservative dose based on the estimated average dietary intake of polyphenols among North Americans, which is one g/day, derived from fruits and vegetables. They gave Tg2576 mice a species-adjusted equivalent dose (200 mg/kg/day), which was delivered in the animals’ drinking water for five months. At the end of that time, the mice displayed a 30-50 percent decrease in oligomers in the brain as judged by immunoblot with A11 antibody, and similar reduction in total Aβ and plaque area. The reduction in pathology was accompanied by an improvement in memory performance in the Morris water maze.

Because the mice showed no evidence of changes in Aβ production or in levels of enzymes that degrade Aβ, the investigators suggest that the pathological and behavioral effects are likely due to the prevention of Aβ oligomerization. The extracts also have antioxidant and anti-inflammatory effects, though, which could contribute to their action. Their activity is distinct from the effects of another component of red wine, resveratrol, which acts through sirtuins to mimic the effect of calorie restriction in aging-related diseases (see ARF related news story).

For those of us who already consider red wine an essential part of any balanced diet, the news is welcome, but Pasinetti cautions that results in mice are only the beginning. “The acid test is, of course, what happens in humans,” he said, noting that his group has already initiated a clinical trial of the extract. He has applied for funding from the NIH to test the extract in a Phase 1/2 pilot study of 50 mild to moderate AD patients. If all goes well, he said, the first patients could begin on the initial dosing study as early as September, using the same material tested in mice. The double-blind, placebo-controlled study will look at tolerability and safety and also include some measures of cognitive function.—Pat McCaffrey

Comments

  1. This is a very interesting paper that strengthens further the notion that natural grape-derived polyphenols may exert potent anti-amyloidogenic effects in vivo. Moderate consumption of red wine is believed to reduce the incidence of dementia and Alzheimer's disease. However, the mechanism by which this particular intervention affects the neurodegenerative process of AD is not clearly understood.
    In this study, Pasinetti and colleagues provide strong evidence by photo-induced cross-linking of unmodified proteins (PICUP) techniques and anti-oligomer immunoblotting that a particular extract of grape seed-derived polyphenols is a potent inhibitor of Aβ oligomerization in vitro and in vivo in mice. This may represent a safe and very efficient approach to counteract amyloid formation.

    View all comments by Philippe Marambaud

  2. This work by Wang and colleagues is very interesting and furthers the notion that polyphenolic compounds may be beneficial against Alzheimer disease. However, as we know, there are often difficulties surrounding these kinds of compounds in the way of bioavailability. Although the authors do address the issue of equivalent doses between mice and humans, it remains to be determined which components of the grape seed extract are responsible for the all around reductions in pathology and subsequently the feasibility of their use based on their pharmacokinetic parameters in humans. Furthermore, it may be beneficial to elucidate the exact therapeutic mechanism involved in the reduction of amyloid burden. The authors suggest that by mobilizing fractions of HMW oligos into monomeric Aβ fractions, grape seed extract may in effect promote clearance, as these monomeric forms preferentially efflux out of the brain. Yet another possibility may be tied to grape seed extract’s ability to reduce LDL, which may consequently free up LRP to mediate Aβ efflux. The authors do not detect an increase in peripheral levels of Aβ, though. Accordingly, another possibility is that grape seed extract promotes intracellular degradation of Aβ similar to that reported of resveratrol by Marambaud et al., 2005. Regardless, this study is a step in the right direction for the development of a nutraceutical that may have therapeutic potential against Alzheimer disease.

    View all comments by Jun Tan

  3. These observations are in line with the current view that polyphenolic dietary supplementation may have an impact on the cognitive function of older individuals affected by cognitive impairments. As a consequence, polyphenol compounds aimed at altering the brain aging processes and serving as possible neuroprotective agents in progressive neurodegenerative disorders should be further investigated in well-controlled randomized studies.

    View all comments by Patricia C. Heyn

  4. I think this paper by Wang et al. is very interesting. It supports the hypothesis that polyphenolic compounds modulate amyloidogenesis and have beneficial effects in AD models. The authors state that their compound extract can significantly inhibit amyloid-β protein aggregation into high-molecular-weight oligomers in vitro (see abstract). It seems to me that the compound extract indeed prevents the formation of large amyloid fibrils; however, its effect on oligomerization is unclear and needs to be worked out much more clearly. More studies with electron microscopy and conformation-specific antibodies and other methods need to be performed to determine the mechanism of action of the compounds. It would be also very useful to know what structure is responsible for the effects in vitro and in vivo. Nevertheless, I think polyphenols could be very useful for therapy development. However, we need to learn much more about their mode of action in the brain of transgenic animals and AD patients.

    View all comments by Erich Wanker

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References

News Citations

  1. A Fortune in Tea Leaves—Extract Blocks Amyloid Formation
  2. Aging, Acetate, and Aβ: Sirtuins Regulate Metabolism and More

Paper Citations

  1. Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des. 2006 Jan;67(1):27-37. PubMed.
  2. Wang J, Ho L, Zhao Z, Seror I, Humala N, Dickstein DL, Thiyagarajan M, Percival SS, Talcott ST, Pasinetti GM. Moderate consumption of Cabernet Sauvignon attenuates Abeta neuropathology in a mouse model of Alzheimer's disease. FASEB J. 2006 Nov;20(13):2313-20. PubMed.

Further Reading

Primary Papers

  1. 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. PubMed.

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