Blood Protein Fibrin Unveiled as Catalyst for Brain Disease

Researchers at the Gladstone Institutes have made a significant breakthrough in understanding the development of neurological diseases such as Alzheimer’s and multiple sclerosis. Their study identifies fibrin, a blood protein, as the key factor responsible for transforming beneficial immune cells in the brain, known as microglia, into harmful cells that contribute to the progression of these diseases.

In individuals afflicted with Alzheimer’s and multiple sclerosis, the immune cells within the brain undergo a detrimental transformation, leading to cognitive dysfunction and impaired motor skills. Furthermore, these harmful immune cells may also play a role in age-related cognitive decline, even in individuals without dementia.

Scientists have long been dedicated to unraveling the triggers and specific roles of microglia in disease progression. By identifying the factors that induce toxicity in microglia, new treatment strategies for neurological diseases could be developed.

The researchers, led by Senior Investigator Katerina Akassoglou, Ph.D., from the Gladstone Institutes, have now demonstrated that exposure to blood leaking into the brain activates harmful genes in microglia, converting them into toxic cells capable of destroying neurons.

Their investigation revealed that fibrin, a blood protein known for aiding in clotting, is responsible for activating these detrimental genes in microglia during both Alzheimer’s disease and multiple sclerosis. The findings, published in the journal Nature Immunology, suggest that counteracting the blood toxicity caused by fibrin could safeguard the brain from harmful inflammation and neuronal loss associated with neurological diseases.

Akassoglou, who also serves as the director of the Center for Neurovascular Brain Immunology at Gladstone and a professor of neurology at UC San Francisco (UCSF), explains, “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. Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases.”

The Impact of Blood Proteins

Patients with neurological diseases like Alzheimer’s and multiple sclerosis exhibit abnormalities in the extensive network of blood vessels in their brain, which allows blood proteins to penetrate areas responsible for cognitive and motor functions. Early blood leaks into the brain have been correlated with worse prognoses for many of these diseases.

To ascertain which blood proteins influence gene and protein changes in immune cells, Akassoglou and her team systematically examined the effects of losing essential blood proteins, including albumin, complement, and fibrin, on immune cells in mice.

Collaborating 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, the researchers utilized advanced molecular and computational technologies to analyze the impact of these blood proteins.

The study revealed that different blood proteins activate distinct molecular processes in microglia. Notably, fibrin was found to be the primary driver of gene and protein activities that render microglia toxic to neurons, while the other blood proteins examined did not have significant contributions to these toxic effects.

Andrew Mendiola, Ph.D., a scientist in Akassoglou’s lab and the first author of the study, says, “We combined cutting-edge tools to capture a broad view of all the microglia processes triggered by distinct blood proteins. Fibrin stood out, as it triggered a dramatic gene response in microglia, which mirrored gene signatures identified in chronic neurological diseases such as Alzheimer’s disease.”

In previous research, Akassoglou and her team discovered that fibrin could activate microglia and induce cognitive impairment in mice. They further identified an inflammatory region within fibrin that was responsible for its negative influence, which did not affect its crucial role in blood clotting. In the current study, the team demonstrated that removing this inflammatory region reduced the ability of fibrin to activate toxic genes in microglia, effectively restoring the protective functions of these immune cells.

Implications for Treatment

To determine the relevance of their findings to disease, the researchers utilized a technique they developed to identify toxic gene activities in cells from mouse models of Alzheimer’s disease and multiple sclerosis. In both models, the genes activated by fibrin in microglia were found to be involved in neurodegeneration and oxidative stress, processes associated with both diseases.

Mendiola emphasizes, “We think that, across neurological diseases, fibrin deposits at sites of blood leaks might drive toxic immune responses. Identifying approaches to selectively inhibit these toxic responses could be a game changer for treating disease.”

Akassoglou’s lab has already developed a therapeutic monoclonal antibody that targets the inflammatory domain of fibrin, effectively blocking its detrimental effects without affecting blood clotting. This antibody has demonstrated protective effects against multiple sclerosis and Alzheimer’s disease in mice. A humanized version of this innovative fibrin immunotherapy has entered Phase 1 safety clinical trials.

Akassoglou adds, “Neutralizing blood toxicity could protect the brain from harmful inflammation and restore neuronal connections required for cognitive functions. By targeting fibrin, we can block toxic microglia cells without affecting their protective functions in the brain.”

The study has generated a wealth of molecular data that is now freely accessible to other researchers. The open-access atlas detailing how blood affects the brain can be further analyzed to uncover additional functions of blood proteins and aid in the discovery of new drugs and biomarkers.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease, comments, “These exciting findings change the way we think about blood proteins, from secondary bystanders to primary drivers of harm in the brain. 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.”

Reference: “Defining blood-induced microglia functions in neurodegeneration through multiomic profiling” by Andrew S. Mendiola, Zhaoqi Yan, Karuna Dixit, Jeffrey R. Johnson, Mehdi Bouhaddou, Anke Meyer-Franke, Min-Gyoung Shin, Yu Yong, Ayushi Agrawal, Eilidh MacDonald, Gayathri Muthukumar, Clairice Pearce, Nikhita Arun, Belinda Cabriga, Rosa Meza-Acevedo, Maria del Pilar S. Alzamora, Scott S. Zamvil, Alexander R. Pico, Jae Kyu Ryu, Nevan J. Krogan and Katerina Akassoglou, 8 June 2023, Nature Immunology.
DOI: 10.1038/s41590-023-01522-0

The study received funding from the National Institutes of Health, the National Multiple Sclerosis Society, and the BrightFocus Foundation.

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More about Neurological diseases

• Gladstone Institutes – Study on Blood and Brain Disease
• Nature Immunology – Research Paper
• UC San Francisco – Center for Neurovascular Brain Immunology