A new study
suggests that in Alzheimer's disease, certain immune cells in the brain
abnormally consume an important nutrient: arginine. Blocking this process with
a small-molecule drug prevented the characteristic brain plaques and memory
loss in a mouse model of the disease. Published in the Journal of Neuroscience,
the research not only points to a new potential cause of Alzheimer's but also
may eventually lead to a new treatment strategy.
The study—published April 15, 2015 in the Journal of
Neuroscience—is attracting national attention for proposing a new potential
cause of Alzheimer’s. Duke researchers, who discovered a way to make the brains
of mice to respond to Alzheimer’s disease similarly to humans, found that in
mice with the disease, immune system cells meant to protect the brain start to
consume an important nutrient: arginine. They were able to slow the disease’s
progress in the mouse model with a small-molecule drug—indicating the eventual
potential for a new treatment strategy.
Past research of the disease has focused on a protein
called beta-amyloid, which creates “plaques” in the brain, rather than
arginine.
“With drugs that affect amyloid, not a single trial has
succeeded,” said Carol Colton, an author of the study and professor of
neurology at the School of Medicine. “It’s time we look at new direction—and
this is a potential direction that nobody has thought of before.”
Although Colton has been researching the immune system’s
role in Alzheimer’s for many years, the breakthrough came when she was able to
develop a mouse model that was more representative of the disease in humans
than other models in the field.
Previously, genetic mutations given to mice led to the
development of plaques in the brain, but failed to replicate the most important
aspects of Alzheimer’s, including neuron death and memory loss, Colton
explained.
“That’s always been frustrating for the field—you
couldn’t really use mice as a springboard for treatment, because you have nothing
to block,” said Matthew Kan, a seventh-year MD/PhD student. “It’s difficult to
study the brain in a living person, but by changing this one gene to make the
mice’s immune systems look more like humans’, we can now ask these questions in
mice that we could in humans.”
In the more human-like system, researchers were able to
observe the mice as they grew old and developed Alzheimer’s disease. They noted
that the immune systems of mice with Alzheimer’s were suppressed, and found low
levels of arginine in their brains.
The team then developed and tested a new drug in the
mice, which blocked the immune pathway that consumes arginine in the brain. The
treated mice showed significantly less memory loss and brain cell death than
the untreated ones after 24 weeks, Colton noted.
Although the team has developed a successful preventative
therapy for mice, they are wary of jumping to conclusions.
“I, as a clinician, cringe at some of the reporting that
I know is going to lead to a lot of false hope,” said James Burke, associate
director of the Bryan Alzheimer’s Disease Research Center at Duke. “If you have
a family member with the disease, you get the idea that this is the next cure.”
Burke emphasized that early animal studies are difficult
to predict because a number of things could go wrong before treatment even
reaches humans. But the study’s potential implications for Alzheimer’s therapy
are still important for opening up the field to novel mechanisms, he said.
Moving forward, the researchers hope to continue testing
the drug’s effectiveness in treating and reversing the Alzheimer’s condition in
mice, although testing the treatment in human clinical trials might be anywhere
from seven to more than 10 years away, Colton said.
”I think there’s still a lot of work for us—to show what
we’ve found in the mice is really what’s happening in humans,” Kan said. “But
we have a great new direction to go in, and a lot of questions to ask.”
Does the study suggest that people should eat more
arginine or take dietary supplements? The answer is 'no,' Colton said, partly
because a dense mesh of cells and blood vessels called the blood-brain barrier
determines how much arginine will enter the brain. Eating more arginine may not
help more get into the sites of the brain that need it. Besides, if the scientists'
theory is correct, then the enzyme arginase, unless it's blocked, would still
break down the arginine.
"We see this study opening the doors to thinking
about Alzheimer's in a completely different way, to break the stalemate of
ideas in AD," Colton said. "The field has been driven by amyloid for
the past 15, 20 years and we have to look at other things because we still do
not understand the mechanism of disease or how to develop effective
therapeutics."
L-arginine is a
chemical building block called “an amino acid.” It is obtained from the diet
and is necessary for the body to make proteins. L-arginine is found in red
meat, poultry, fish, and dairy products. It can also be made in a laboratory
and used as medicine. L-arginine is converted in the body into a chemical
called nitric oxide. Nitric oxide causes blood vessels to open wider for
improved blood flow. L-arginine also stimulates the release of growth hormone,
insulin, and other substances in the body.
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