A follow-up study investigating the effects of resveratrol on Alzheimer's disease brings new detail regarding the immune response within the brain. Although it is not being heralded as a cure, the molecule and its effects will help focus further research.
Yet, currently, the exact mechanisms behind Alzheimer's are not fully understood, and modern treatments only address the symptoms.
These sobering facts make Alzheimer's research a hotbed of innovation. Any potential avenue is thoroughly investigated, and no molecule is left unturned.
The findings of the latest Alzheimer's study were presented at the Alzheimer's Association International Conference 2016 in Toronto, Canada, yesterday. The molecule of interest was resveratrol.
What is resveratrol?
Resveratrol is a natural phenol, released by certain plants in response to attack or injury. The compound is found in a number of foods, including grapes, blueberries, raspberries, red wine, and dark chocolate.
Caloric restriction is known to reduce age-related diseases in animals, and resveratrol is known to mimic caloric restriction; it does this by releasing the same proteins - sirtuins - hence the molecule's interest to those studying neurodegenerative, age-related disease.
In 2015, the largest nationwide clinical trial on high-dosage resveratrol was published in Neurology. The researchers found that long-term resveratrol treatment of individuals with mild to moderate Alzheimer's appeared to stop, or at least slow, the progress of the disease.
A protein called amyloid-beta40 (Abeta40) is known to decline as dementia worsens. The study in 2015 showed that, in individuals who took resveratrol, the Abeta40 levels remained stable, whereas the placebo group's levels dropped.
At the time, principal investigator Dr. R. Scott Turner warned: "This is a single, small study with findings that call for further research to interpret properly."
Dr. Turner was the lead investigator of the current study, along with neurologist Dr. Charbel Moussa, scientific and clinical research director of the GUMC Translational Neurotherapeutics Program. For this round of trials, the team was interested in the levels of specific molecules in the cerebrospinal fluid (CSF) of Alzheimer's patients.
In all, 19 participants received a daily dose of resveratrol (the equivalent to 1,000 bottles of red wine) and another 19 were given a placebo.
Uncovering the anti-inflammatory effects of resveratrol
The brains of individuals with Alzheimer's are damaged by inflammation. This inflammation is thought to be because of a reaction to the buildup of proteins in the brain, including Abeta40 and Abeta42.
Increased inflammation appears to worsen the disease. Previously, this inflammation was considered to come only from immune cells within the brain. The current study hints that this might not be the case.
The primary molecule of interest to the researchers was matrix metalloproteinase-9 (MMP-9). The team found a 50 percent reduction of MMP-9 in the CSF of those taking the daily resveratrol dose.
This is significant because MMP-9 is reduced when sirtuin1 (one of the proteins linked to caloric restriction) is activated. Higher levels of MMP-9 are known to cause a breakdown of the blood-brain barrier - a blockade that normally prevents proteins and other molecules from entering the brain.
Additionally, the team found that resveratrol increased levels of compounds linked to a long-term "adaptive" immune response; this suggests an involvement of inflammatory cells that are resident in the brain. This type of reaction degrades and removes neurotoxic proteins.
"These new findings are exciting because they increase our understanding of how resveratrol may be clinically beneficial to individuals with Alzheimer's disease. In particular, they point to the important role of inflammation in the disease and the potent anti-inflammatory effects of resveratrol."
Dr. Scott Turner
More questions to be answered
Although resveratrol is unlikely to be a treatment on its own (it does not prevent tau proteins from attacking and destroying neurons), a phase III trial is planned. Not only have the recent studies given insight into the disease, but they are also throwing out other questions that require answers.
For instance, Dr. Turner explains another of the mysteries to be uncovered: "A puzzling finding from the resveratrol study (as well as immunotherapy strategies for Alzheimer's under investigation) is the greater shrinkage of the brain found with treatment. These new findings support the notion that resveratrol decreases swelling that results from inflammation in Alzheimer's brain."
This "seemingly paradoxical" finding has also been described in drugs used to treat individuals with multiple sclerosis, another brain disease that involves high levels of inflammation.
Alzheimer's is a complicated disease, and it will only be through concerted effort that its secrets are finally revealed, and improved treatments are designed.