When Microglia Turn Toxic: How Blood Protein Fibrin is Responsible for Harmful Brain Inflammation

Sunday - June 25 2023, 04:00 UTC - 1 year ago

Researchers at Gladstone Institutes led by Senior Investigator Katerina Akassoglou, Ph.D. found that a blood protein called fibrin—which normally aids blood clotting—is responsible for turning on the detrimental genes in microglia, both in Alzheimer’s disease and multiple sclerosis. The findings suggest that counteracting the blood toxicity caused by fibrin can protect the brain from harmful inflammation and loss of neurons in neurological diseases.

In individuals suffering from neurological disorders such as Alzheimer’s and Multiple Sclerosis, beneficial microglia, the immune cells within the brain, turn harmful to neurons. This detrimental shift contributes to cognitive dysfunction and impaired motor skills. Additionally, these harmful immune cells might play a role in cognitive decline associated with aging in individuals who are not suffering from dementia.

For a while, researchers have been diligently working to comprehend what precisely prompts these beneficial microglia to become harmful, and their specific role in disease progression. If they could identify what makes microglia toxic, they could find new ways to treat neurological diseases.

Now, researchers at Gladstone Institutes led by Senior Investigator Katerina Akassoglou, Ph.D., showed that exposure to blood leaking into the brain turns on harmful genes in microglia, transforming them into toxic cells that can destroy neurons.

The scientists discovered that a blood protein called fibrin—which normally aids blood clotting—is responsible for turning on the detrimental genes in microglia, both in Alzheimer’s disease and multiple sclerosis. The findings, published in the journal Nature Immunology, suggest that counteracting the blood toxicity caused by fibrin can protect the brain from harmful inflammation and loss of neurons in neurological diseases.

"Our study answers, for the first time in a comprehensive way, how blood that leaks into the brain hijacks the brain’s immune system to cause toxic effects in brain diseases," says Akassoglou, who is also director of the Center for Neurovascular Brain Immunology at Gladstone and a professor of neurology at UC San Francisco (UCSF). "Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases." .

Individuals with neurological diseases like Alzheimer’s disease and multiple sclerosis have abnormalities within the vast network of blood vessels in their brain, which allow blood proteins to seep into brain areas responsible for cognitive and motor functions. Blood leaks in the brain occur early and correlate with worse prognosis in many of these diseases.

To understand which proteins in the blood affect gene and protein changes in immune cells, Akassoglou and her team took a systematic approach to determine how losing key blood proteins—such as albumin, complement, and fibrin—would affect immune cells in mice.

They analyzed the effect of the blood proteins with a suite of advanced molecular and computational technologies in collaboration with Nevan Krogan, Ph.D., senior investigator at Gladstone and director of the Quantitative Biosciences Institute at UCSF, and Alex Pico, Ph.D., research investigator and director of the Bioinformatics Core at Gladstone.

In the new study, the researchers found that different blood proteins activate distinct molecular processes in microglia. What’s more, they identified that fibrin is responsible for driving unique gene and protein activities that make microglia toxic to neurons. The other blood proteins tested were not mainly responsible for these toxic effects.

"We combine specially bred mouse models of Alzheimer’s and multiple sclerosis, advanced molecular approaches, and state-of-the-art computational methods to learn more about the mechanisms driving these diseases," says Pico. "Our findings have revealed a new therapeutic strategy to treat diseases rooted in a malfunctioning immune system in the brain." .