RESEARCH
Katerina Akassoglou’s lab pioneered studies on neurovascular regulation of inflammation and tissue repair and the molecular interface blood proteins utilize to interact with nervous system cells. The Akassoglou lab discovered the coagulation factor fibrinogen as a blood-derived driver for microglia activation in a wide range of neurologic diseases, such as multiple sclerosis, Alzheimer’s disease, COVID-19, and brain trauma. By developing a multiomic and genetic loss-of-function pipeline, we reported the transcriptomic and global phosphoproteomic landscape of blood-induced microglia activation and the causal role for fibrin in induction of neurodegenerative genes and oxidative stress pathways in innate immune cells. The Akassoglou lab discovered a novel homeostatic role for microglia in the regulation of neuronal synchronization and control of hyperexcitability. The Akassoglou lab discovered a first-in-class fibrin-targeting immunotherapy, currently being tested in clinical trials, to selectively target inflammatory functions of fibrin without interference with clotting with potent therapeutic effects in autoimmune-, amyloid-, and viral-driven neurotoxicity.
Our work has led to a new way of thinking about neurological diseases by proposing a fundamental mechanism through which cerebrovascular dysfunction impairs the brain and spinal cord. Specifically, they demonstrated that the neurovascular interface is fundamentally changed in neurological disease, resulting in increased blood-brain barrier permeability that promotes toxic brain inflammation. They identified the blood clotting factor fibrinogen as a common driver for neuroinflammation and neurodegeneration and inhibitor of neurorepair. They developed the first immunotherapy, currently in Phase 1 Trials, that blocks the deleterious functions of fibrin and protects from neuroinflammation and neurodegeneration in animal models of multiple sclerosis, Alzheimer’s disease, and COVID-19. Therefore, the team’s research has broad impact on the understanding of and ability to treat multiple neurological diseases, including multiple sclerosis, stroke, epilepsy, traumatic brain injury, and spinal cord injury.
Review Articles
- Akassoglou K, Davalos D, Mendiola AS, Petersen MA, Ryu JK, Schachtrup C, Yan Z. Pioneering discovery and therapeutics at the brain-vascular-immune interface. Cell 2024, 187(21):5871-5876.
- Akassoglou, K. The immunology of blood: Connecting the dots at the neurovascular interface. Nat Immunol 2020, 21:710-712. Invited Essay in the 20th Anniversary Issue of Nat Immunol
- Petersen MA, Ryu JK, Akassoglou K. Fibrinogen in neurological diseases: mechanisms, imaging, and therapeutics. Nat Rev Neurosci 2018, 19(5):283-301.
- Davalos D, Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 2012, 34:43-62.
Current support for our research by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) R35 Research Program Award, the National Multiple Sclerosis Society (NMSS), the Conrad N. Hilton Foundation, The Department of Defense (DoD), and Gladstone Institutes.
Junior Faculty and trainees are kindly supported by Young Investigator Awards and Postdoctoral Fellowships from: Race to Erase MS, American Heart Association, the National Multiple Sclerosis Society (NMSS), the Thrasher Foundation, the NIH National Institute of Child Health and Human Development (NICHD), National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS).
Over the years our research has been possible by grants from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS), the National Multiple Sclerosis Society (NMSS), the Dana Foundation, the Department of Defense (DoD), the Christopher and Dana Reeve Foundation, FastForward/NMSS, Lundbeck, The Bechtel Foundation, UCSF Diabetes and Endocrinology Research Center, and the UCSF Liver Center. Trainees in the lab have been supported by NMSS, the German Research Foundation (DFG), the Spanish Research Foundation, the Pediatric Scientist Development Program fellowship (supported by March of Dimes and NIH/NICHD), and NIH training grants.
