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, say researchers at Georgetown University
Medical Center. 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. According to the researchers, 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,
scientific and clinical research director of the GUMC Translational
Neurotherapeutics Program. "These are very exciting findings because it
shows that resveratrol engages the brain in a measurable way, and that the
immune response to Alzheimer's disease comes, in part, from outside the
brain."
Resveratrol is a naturally occurring
compound found in foods such as red grapes, red wine, raspberries and dark
chocolate. GUMC researchers, led by R. Scott Turner, MD, PhD, 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 study was published Sept.
11, 2015 in Neurology.
The new part of the resveratrol study
examines specific molecules in the cerebrospinal fluid (CSF) taken 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 two-thirds 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 that treated patients had a 50 percent reduction in matrix
metalloproteinase-9 (MMP-9) levels in the cerebrospinal fluid. MMP-9 is
decreased when sirtuin1 (SIRT1) is activated. High levels of 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, say
the researchers.
"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," 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, says Moussa. "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.
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