Resveratrol, given to Alzheimer’s patients, appears to restore the integrity of the blood-brain barrier, reducing the ability of harmful immune molecules secreted by immune cells to infiltrate from the body into brain tissues. The reduction in neuronal inflammation slowed the cognitive decline of patients, compared to a matching group of placebo-treated patients with the disorder. The laboratory data provide a more complete picture of results from a clinical trial studying resveratrol in Alzheimer’s disease that was first reported in 2015. The new findings will be presented at the Alzheimer’s Association International Conference 2016 in Toronto on July 27th.
The Alzheimer’s disease brain is damaged by inflammation, thought to be due to a reaction to the buildup of abnormal proteins, including Abeta40 and Abeta42, linked to destruction of neurons. Researchers believe that heightened inflammation – which was historically thought to come only from “resident” brain immune cells – worsens the disease. This study suggests that some of the immune molecules that can cause inflammation in the blood can enter the brain through a leaky blood-brain barrier.
“These findings suggest that resveratrol imposes a kind of crowd control at the border of the brain. The agent seems to shut out unwanted immune molecules that can exacerbate brain inflammation and kill neurons,” says neurologist Charbel Moussa, MD, PhD.
Resveratrol is a naturally occurring compound found in red grapes, red wine, raspberries and dark chocolate. GUMC researchers tested the substance in 119 patients, the largest nationwide phase II clinical trial to study high-dose pure synthetic (pharmaceutical-grade) resveratrol in individuals with mild to moderate Alzheimer’s. The new part of the resveratrol study examines specific molecules in the CSF from participants with biomarker-confirmed Alzheimer’s disease – 19 were given a placebo, and 19 treated daily for a year with resveratrol, equivalent to the amount found in about 1,000 bottles of red wine.
Previous studies with animals found that age-related diseases-including Alzheimer’s – can be prevented or delayed by long-term caloric restriction (consuming 2/3 the normal caloric intake). The researchers studied resveratrol because it mimics the effects of caloric restriction by also activating proteins called sirtuins.
In this new study, Moussa and Turner found treated patients had a 50% reduction in matrix metalloproteinase-9 (MMP-9) levels in CSF. MMP-9 is decreased when sirtuin1 (SIRT1) is activated. High MMP-9 cause a breakdown in the blood-brain barrier, allowing proteins and molecules from the body to enter the brain. Normally low MMP-9 levels maintain the barrier.
They point to the important role of inflammation in the disease, and the potent anti-inflammatory effects of resveratrol,” says Turner, director of GUMC’s Memory Disorders Program and co-director of the Translational Neurotherapeutics Program.
They also found that resveratrol increased the level of molecules linked to a long-term beneficial or “adaptive” immune reaction, suggesting involvement of inflammatory cells that are resident in the brain. “This is the kind of immune response you want – it is there to remove and degrade neurotoxic proteins.”
“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,” says Turner. “This seemingly paradoxical effect is also found with many of the drugs that are beneficial for patients with multiple sclerosis – another brain disease characterized by excessive inflammation.”
Moussa says that resveratrol should be further tested in a phase III study, but the agent, by itself, is unlikely to be a complete treatment for Alzheimer’s. It does not inhibit destruction of brain neurons by tau, another protein aggregate involved in the disease, so a likely beneficial treatment would combine resveratrol with an agent that targets tau, he says. http://www.eurekalert.org/pub_releases/2016-07/gumc-rrb072216.php
Recent Comments