Arginine May Be A Cause and Therapeutic Target for Alzheimer’s Disease in Mice

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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neuronsA new study published in the Journal of Neuroscience revealed that specific immune cells and degradation of a nutrient called arginine might be linked to Alzheimer’s disease development. The study was performed by researchers at Duke University Medical Center, the West Virginia University School of Medicine and the University of Washington, and is entitled “Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer’s Disease.

Alzheimer’s disease is a neurodegenerative disorder where individuals initially experience memory loss and confusion that gradually leads to behavior and personality changes, a decline in cognitive abilities, and ultimately the severe loss of mental function. The disease is characterized by the loss of neurons responsible for memory and learning, and brain formation of amyloid plaques (containing sticky beta-amyloid proteins) and tangles (twisted strands of a protein called tau). The body’s immune system is thought to play a role in Alzheimer’s disease pathogenesis, although the link between immunity and this neurodegenerative disorder is not clear.

In this study, researchers used a specific mouse model (CVN-AD), which has been engineered to have an immune system more similar to the one found in humans. The CVN-AD mouse model can develop features of human Alzheimer’s disease, namely plaques and tangles in the brain, neuronal loss and behavior changes.

By searching for immune anomalies throughout the lifespan of CVN-AD mice, researchers found that the majority of the immune components remain the same, with one exception: microglia. Microglia is a type of brain-resident white blood cell that acts as the main immune defense mechanism in the central nervous system (brain and spinal cord). In CVN-AD mice, microglia was found to divide and change early in the disease course. By analyzing gene activity patterns in microglia cells, a higher expression of genes linked to immunosuppression and a reduced expression of genes that stimulate the immune system were both observed.

“It’s surprising, because [suppression of the immune system is] not what the field has been thinking is happening in Alzheimer’s disease,” said the study’s first author Matthew Kan in a news release. The general idea is that the brain releases molecules that boost the immune system, potentially leading to brain tissue damage.

The team found a high expression of microglia in the memory-related mouse brain regions where neurons had died, along with a high expression of arginase, an enzyme that breaks down an important amino acid called arginine. Microglia was found to abnormally consume arginine, and as the study’s senior author Dr. Carol Colton noted, “If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease.”

Interestingly, researchers found that by blocking arginase with a small-molecule drug called difluoromethylornithine (DFMO) prior to the development of disease-related symptoms, it was possible to prevent the formation of brain plaques, microglia activation and memory loss in mice.

“All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect—the mouse, at least—from Alzheimer’s disease,” noted Kan. The research team concluded that their findings suggest a new potential cause for Alzheimer’s disease development and could lead to potential new therapeutic strategies.

DFMO is currently being tested as a cancer therapy in human clinical trials. The team plans to evaluate it as a potential therapy for Alzheimer’s disease after the disease-related symptoms have developed.

“We see this study opening the doors to thinking about Alzheimer’s in a completely different way, to break the stalemate of ideas in Alzheimer’s disease,” said Dr. Colton. “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.”