A blood-clotting protein called fibrin can activate immune cells in the brain and contribute to inflammation and neurodegeneration in multiple sclerosis (MS), a study revealed. Because blood vessels become leaky in neurodegenerative conditions like MS, the blood can cross into the brain, which is known to activate multiple pro-inflammatory processes. Researchers have identified fibrin as the component in blood that triggers the damaging inflammation that results from these leaks, suggesting it may be a promising target for treating inflammatory and neurological diseases, the researchers said. "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," Katerina Akassoglou, PhD, study lead author and director of the Center for Neurovascular Brain Immunology at Gladstone Institutes, said in a press release. "Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases." Akassoglou is also a professor of neurology at University of California San Francisco. The study, "Defining blood-induced microglia functions in neurodegeneration through multiomic profiling," was published in Nature Immunology. Abnormal activation of microglia, the brain's resident immune cells, contributes to inflammation and damage in multiple conditions affecting the brain, including MS and Alzheimer's disease. An early feature in such conditions is the disruption of the blood-brain barrier (BBB), the highly selective membrane that shields the brain and spinal cord from large molecules and pathogens circulating in the blood. Damage to the BBB allows blood to seep into the brain and activate microglia, a process that correlates with worse outcomes. It hasn't been known which blood proteins leak into the brain and trigger harmful microglia activities, leading Akassoglou's research team to delete individual proteins to determine the impact on immune cells using cells and animal models. Normal blood with all proteins induced widespread changes in the genes associated with the harmful activation of microglia and oxidative stress, a form of damage caused by the accumulation of oxygen free radicals generated by metabolism. These toxic processes were largely suppressed when fibrin — a fibrous protein involved in blood clotting — was deleted. Fibrin's role in MS brain inflammation. Treating mouse immune cells with fibrin recapitulated many processes seen with whole blood, stimulating oxidative stress genes and activating pro-inflammatory features. "We combined cutting-edge tools to capture a broad view of all the microglia processes triggered by distinct blood proteins," said Andrew Mendiola, PhD, a scientist in Akassoglou's lab and the study's first author. "Fibrin stood out, as it triggered a dramatic gene response in microglia, which mirrored gene signatures identified in chronic neurological diseases." Mouse models of MS are known to have immune cell subsets that contribute to oxidative stress. Stimulation with fibrin generated the same oxidative stress signature in microglia. Similar findings were seen in a mouse model of Alzheimer's disease. The region in fibrin responsible for driving oxidative stress was independent of its blood clotting properties, the researchers found in later experiments. Indeed, mice lacking the portion of fibrin that interacts with immune cell receptors had less oxidative stress and nerve cell damage, and were protected from paralysis, but retained normal blood clotting. Removing this portion decreased fibrin's ability to stimulate harmful genes in microglia and returned microglia to a normal protective state. "We think that, across neurological diseases, fibrin deposits at sites of blood leaks might drive toxic immune responses," Mendiola said. "Identifying approaches to selectively inhibit these toxic responses could be a game changer for treating disease." Akassoglou's team has developed an antibody-based therapeutic to target this pro-inflammatory portion of fibrin. A version of it is being evaluated in Phase 1 clinical trials in people with Alzheimer's. "Neutralizing blood toxicity could protect the brain from harmful inflammation and restore neuronal connections required for cognitive functions," Akassoglou said. "By targeting fibrin, we can block toxic microglia cells without affecting their protective functions in the brain." Finally, experiments confirmed shared fibrin-induced microglia oxidative stress signatures in both MS and Alzheimer's mouse models. "We defined fibrin as a unique blood protein required for microglial polarization to oxidative stress and neurodegenerative phenotypes [characteristics] in MS and AD mice," the researchers said. "Our data provide an interactive resource for investigation of the immunology of blood proteins that could support therapeutic targeting of microglia activation by immune and vascular signals." "These exciting findings change the way we think about blood proteins, from secondary bystanders to primary drivers of harm in the brain," said Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease. "The mechanisms identified in this study could be at work in a range of neurological conditions involving blood leaks in the brain, including neurodegenerative disorders, autoimmune diseases, stroke, and traumatic brain injury. Therefore, they have far-reaching therapeutic implications."