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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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The Feinstein Institute for Medical Research - North-Shore LIJ
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.
University of South Florida
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.
University of Colorado Anschultz Medical Campus
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.
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.
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