Wednesday, February 25, 2015

Do the Anti-Alzheimer's Effects of Grape Seed Extract (GSE) Start in the Gut? Your Gut Bugs Could Save Your Brain

The gut may be the missing piece to the Alzheimer's puzzle.
It is well-established that an phenolic extract from the seeds of grapes (GSPE) can have significant anti-Alzheimer's and general neuroptective and anti-dementia effects (Sarkaki. 2007; Balu. 2005; Wang. 2009).

In their latest study, scientists from the University of Queensland did now, for the first time, investigate the role your intestinal microbiota may play in the metabolism and production of orally ingested and newly formed polyphenolic compounds that will then mediate the attenuation of Alzheimer’s disease β-amyloid oligomerization.
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While it is well-known hat the intestinal microbiota is known to actively convert many dietary polyphenols, including GSPE, to phenolic acids, there has as of now been very limited information on the bioavailability and bioactivity of GSPE-derived phenolic acid in the brain.

The latter, i.e. the ability of these compounds to actually make it into the brain, however, is of obvious importance for them to elicit any of those impressive effects that have previously been observed in the petri dish or with direct injection into the brain of rodents. To know, whether the intestinal metabolism of orally ingested grape seed polyphenol extracts (GPSEs) will impair or maybe even increase the uptake and metabolism and thus the effect of grape seed extracts is therefore of utmost importance.
No, "Microbiomes", that's no typo. We host bacteria all over and in us (Cho. 2012)
Grape seed extracts are not the only link between our microbiomes and Alzheimer's disease: Previous research clearly suggest that an unhealthy oral microbiome predisposes to dementia and Alzheimer's (Shoemark. 2015). And Hill et al. who establish in their latest review that "{t]he potential contribution of pathogenic microbes to aging and AD is becoming increasingly recognized (Miklossy, 2011; Cho and Blaser, 2012; Bhattacharjee and Lukiw, 2013; Poole et al., 2013; Heintz and Mair, 2014; Huang et al., 2014; Mancuso et al., 2014)", believe that the similarity of the pathology of Alzheimer's which includes inflammation, brain cell atrophy, immunological aberrations, amyloidogenesis, altered gene expression and cognitive deficits and the symptoms of can hardly be coincidental (Hill. 2014).
Accordingly, the same goes for what would happen to the 12 phenolic of which scientists had previously found that they would be produced by common gut bacteria when they metabolize orally administered GSPE.
Figure 1: Tentative metabolic route of GSPE PAC and molecular formulas of PAC derived phenolic acids (left | Wang. 2015); illustration of the general mechanism of action.
As the results of the study at hand show, only two of them, i.e.3-hydroxybenzoic acid (3-HBA) and 3-(3´-hydroxyphenyl) propionic acid (3-HPP) actually make it into the brains of mice who are orally gavaged with either 25mg/kg or 250mg/kg (for humans that's 160mg/day or 1,600mg/day) where they accumulate atµM concentrations that would be high enough to explain the beneficial effects scientists observed in previous rodent and huma studies.
Figure 2: The electron microscopy images show quite clearly that both GSPE metabolites inhibit the dangerous crosslinking of β-amyloid (Aβ) peptides into neurotoxic Aβ aggregates which renders originally "harmless" plague into a debilitating toxin (Wang. 2015). 
The latter is not surprising, by the way. Want et al. were after all able to show that both, 3-HBA and 3-HPP, potently interfere with the assembly of β-amyloid (Aβ) peptides into neurotoxic Aβ aggregates that play key roles in AD pathogenesis.
What does this mean? While it may at first not be relevant how exactly GPSE supplements may protect you from Alzheimer's disease, the results of the study at hand do have two very important implications:

Previous studies, likewise covered here at the SuppVersity indicate that "1.3g of Grape-Seed Extract Could Protect You From Oxidative Damage, Viral Infections, Obesity and Insulin Resistance, Reduce Your Heart Rate and Blood Pressure and Increase Your Nitric Oxide Production by a Whopping  >25%" | read more
Firstly, for medical treatments one could use ready-made supplements or injections of 3-hydroxybenzoic acid (3-HBA) and 3-(3´-hydroxyphenyl) propionic acid (3-HPP) to elicit maximal protective effects. This would probably not help us to cure, but maybe to stop the progress of dementia.

Secondly, the efficacy of GPSE supplements as Alzheimer's protectants may well depend on the "correct" make-up of your gut microbiome. Assuming you have the wrong or too few of the right bacteria, the conversion to 3-hydroxybenzoic acid (3-HBA) and 3-(3´-hydroxyphenyl) propionic acid (3-HPP) may be so compromised that the protective effect is lost. It would thus be interesting to see which bacteria, exactly are doing the trick to estimate whether or not there may be people who are at risk of getting no benefit out of GSPE supplementation... which happens to be anti-microbial (=kills bacteria) in itself (Baydar. 2006; Sivarooban. 2008), by the way | Comment on Facebook!
References:
  • Balu, Muthaiya, et al. "Age-related oxidative protein damages in central nervous system of rats: modulatory role of grape seed extract." International journal of developmental neuroscience 23.6 (2005): 501-507.
  • Baydar, Nilgun Gokturk, et al. "Determination of antibacterial effects and total phenolic contents of grape (Vitis vinifera L.) seed extracts." International journal of food science & technology 41.7 (2006): 799-804.
  • Bhattacharjee, Surjyadipta, and Walter J. Lukiw. "Alzheimer's disease and the microbiome." Frontiers in cellular neuroscience 7 (2013).
  • Cho, Ilseung, and Martin J. Blaser. "The human microbiome: at the interface of health and disease." Nature Reviews Genetics 13.4 (2012): 260-270.
  • Heintz, Caroline, and William Mair. "You are what you host: microbiome modulation of the aging process." Cell 156.3 (2014): 408-411.
  • Huang, Wei-Shih, et al. "Association between Helicobacter pylori infection and dementia." Journal of Clinical Neuroscience 21.8 (2014): 1355-1358.
  • Hill, James M., et al. "Pathogenic microbes, the microbiome, and Alzheimer’s disease (AD)." Frontiers in aging neuroscience 6 (2014).
  • Mancuso, Roberta, et al. "Titers of Herpes Simplex Virus Type 1 Antibodies Positively Correlate with Grey Matter Volumes in Alzheimer's Disease." Journal of Alzheimer's Disease 38.4 (2014): 741-745.
  • Miklossy, Judith. "Emerging roles of pathogens in Alzheimer disease." Expert reviews in molecular medicine 13 (2011): e30.
  • Poole, Sophie, et al. "Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue." Journal of Alzheimer's Disease 36.4 (2013): 665-677.
  • Sarkaki, Alireza, Yaghoub Farbood, and Mohammad Badavi. "The effect of grape seed extract (GSE) on spatial memory in aged male rats." Pakistan Journal of Medical Sciences 23.4 (2007): 561.
  • Shoemark, Deborah K., and Shelley J. Allen. "The Microbiome and Disease: Reviewing the Links between the Oral Microbiome, Aging, and Alzheimer's Disease." Journal of Alzheimer's Disease 43.3 (2015): 725-738.
  • Sivarooban, T., N. S. Hettiarachchy, and M. G. Johnson. "Physical and antimicrobial properties of grape seed extract, nisin, and EDTA incorporated soy protein edible films." Food Research International 41.8 (2008): 781-785.
  • Wang, Yan-Jiang, et al. "Consumption of grape seed extract prevents amyloid-β deposition and attenuates inflammation in brain of an Alzheimer’s disease mouse." Neurotoxicity research 15.1 (2009): 3-14.
  • Wang, Dongjie, et al. "Role of intestinal microbiota in the generation of polyphenol derived phenolic acid mediated attenuation of Alzheimer's disease β‐amyloid oligomerization." Molecular Nutrition & Food Research (2015).