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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