28 June 2008. 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.
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. Abstract