ARTICLE IN BRIEF
Katerina Akassoglou, PhD, discusses her work investigating the role of fibrinogen and the brain's innate immune response in neurologic disease, and how receiving the NINDS Research Program Award will further her work.
In September, Katerina Akassoglou, PhD, senior investigator at the Gladstone Institutes of Neurological Disease and professor of neurology at the University of California, San Francisco (UCSF), received the National Institute of Neurological Disorders and Stroke (NINDS) Research Program Award for her groundbreaking work investigating the intersection of the brain, immune and vascular systems in neurologic diseases. The $5.8 million grant, which provides longer term support and increased flexibility to researchers who have made significant contributions to neuroscience, will be administered over the next eight years. Dr. Akassoglou spoke with Neurology Today about her career trajectory and how this grant will further her research.
Applying for the NINDS Research Program Award is not unlike applying for any other grant. One applies, awaits review, then receives notice of whether the grant has been awarded. The process was straightforward and familiar to Dr. Akassoglou, who has been awarded many research grants throughout her career. But what is unique about the Research Program Award is its magnitude and flexibility. This relatively new grant from the National Institutes of Health awards nearly $6 million over eight years, allowing for more stability and support for high-risk projects than a typical research grant, she says.
Dr. Akassoglou felt honored to receive the award in September of this year. The funds would allow her to continue her work investigating the role of blood proteins in inflammatory processes in the brain in neurovascular disease — an approach that involves exploring “basic mechanisms of how blood-brain barrier dysfunction affects glia and neuronal cells, and how blood-brain barrier dysfunction affects communication between the brain and the peripheral immune system,” she told Neurology Today.
“We have also found that working at the interface between the blood and the brain is a rich area for novel imaging approaches. We're implementing new imaging technologies to be able to see this process in real time in the brain, and advanced microscopy techniques that allow us to reconstruct blood vessels and neurons in the whole brain.”
EARLY LIFE AND CAREER
Dr. Akassoglou's interest in research at the intersection of neurology, neurobiology, and immunology goes back decades. Born in Athens, Greece, the only child of a mechanic and a seamstress, she was a curious child who was always interested in science. She was also the first in her family to attend high school, and later university.
“My parents were born in the midst of World War II,” Dr. Akassoglou said. “Their generation didn't have the opportunities that I had. My parents were incredibly supportive. Like most parents of their generation, they wanted their children to have the opportunities that they didn't manage to have.”
She was exposed to science for the first time in high school, and she was immediately enchanted. “I had a biology teacher who also had a PhD in immunology, and she got me my first summer internship in a lab. That was the point of no return. Once I started working there, I knew that that was what I wanted to do.”
Dr. Akassoglou received an bachelor's degree in biology at the University of Athens in 1994 and completed a PhD in neurobiology at the University of Athens in 1998 with training in neuropathology at the University of Vienna in 1996. Her research initially focused on transgenic mice expressing tumor necrosis factor (TNF) in the brain, but soon branched out into the work with multiple sclerosis (MS) models that would characterize her career.
“When I started my PhD, my lab was making transgenic mice for TNF,” Dr. Akassoglou explained. “Most of the mice expressing TNF would develop arthritis, but there was one mouse that was paralyzed that didn't have arthritis. I was tasked with figuring out what was wrong with it.”
She discovered that cytokine was overexpressed in the brain of the mouse, to detrimental effect. This led to her development of a new animal model for MS.
“I'm very fortunate that I received equal training in immunology and neurobiology,” Dr. Akassoglou said. “It was clear to me that we cannot just study brain diseases in isolation from the immune system and the vascular system. It was clear that the immune system and the blood-brain barrier would be two key aspects to follow if we wanted to understand and cure neurologic diseases.”
FIBRINOGEN IN NEUROLOGIC DISEASE
Dr. Akassoglou moved to New York in 1998 to conduct postdoctoral research at Rockefeller University under Sidney Strickland, PhD. She also did a second postdoc at New York University in the lab of Moses V. Chao, PhD. During this time, she began to investigate the role of the blood protein fibrinogen, which contributes to clotting, in neurologic disease.
“Neuropathologists were already using fibrinogen as a marker of blood-brain barrier disruption,” Dr. Akassoglou said. “A lot of evidence existed in human MS of the presence of fibrinogen in the brain. I was surprised that there had never been a study to look at whether this protein actually plays a role in the disease. There is also a lot of epidemiology linking disease progression with opening of the blood-brain barrier, but there is always the chicken-and-the-egg question: Is it a cause or a consequence of the neuropathology?”
Together, these data suggested to Dr. Akassoglou that fibrinogen was ripe for further study. “The other thing that caught my attention was that it was described by immunologists as a ligand — an activator of one of the key inflammation receptors that is expressed in microglia cells, complement receptor 3,” she said. “I was absolutely fascinated by the fact that there was a protein from the blood that could enter the brain and potentially activate the brain's innate immune response. I hypothesized that when fibrinogen gets in the brain, it could hijack these brain receptors and transform these microglia cells from physiological cells to pro-inflammatory cells that might be doing damage.”
To test this hypothesis, Dr. Akassoglou and colleagues knocked out fibrinogen in a mouse model of peripheral nerve injury. “We found significant increased repair in the nervous system after fibrinogen depletion,” she said. “It was really the first evidence that this protein plays a role in the context of neurologic disease.” The results were published in Neuron in 2002.
Dr. Akassoglou established her laboratory at the University of California, San Diego (UCSD) in 2003, where she and her colleagues continued to investigate the interactions between fibrinogen and the brain's immune system, particularly in mouse models of multiple sclerosis. “We showed that when we deplete fibrinogen, there is a robust anti-inflammatory effect by suppressing the activation of microglia cells and their toxic functions toward neurons. A really surprising finding was that this protein is actually required for the activation of microglia cells and their transition to cells with toxic properties.” The results were published in the Journal of Experimental Medicine in 2007.
NOVEL IMAGING TOOLS YIELD NEW DISCOVERIES
As she began working with fibrinogen and microglia, “it was critical for us to start imaging,” Dr. Akassoglou said. “We knew these cells were very highly dynamic. However, how they related to the brain's vasculature and the dynamic interactions between the brain's innate immune response and the brain's blood vessels in health and disease was really a black box.” To truly understand these interactions in mouse models of multiple sclerosis, “it would be crucial to image the mouse spinal cord and see blood-brain barrier disruption and demyelination in real time.”
Dr. Akassoglou moved to the Gladstone Institutes and the UCSF in 2008, and established the Gladstone Center for In Vivo Imaging Research in 2010. There, she began using high-resolution two-photon microscopy to image the spinal cord in vivo in transgenic mice with fluorescently labeled microglia, T cells, and fibrinogen. A long-standing collaboration with the National Center for Microscopy and Imaging Research at UCSD further supported these studies.
She and her colleagues discovered that in MS, microglia change shape and cluster around blood vessels very early on in disease pathology — a result that aligned with data in humans with MS suggesting that the opening of the blood-brain barrier, and subsequent leakage of fibrinogen and activation of microglia, may occur in the pre-clinical stage of disease. Her lab also developed novel molecular probes that could detect procoagulant activity in the brain, which further affirmed these findings.
In a paper published in Nature Communications in 2012, Dr. Akassoglou and colleagues demonstrated that fibrinogen activates microglia by binding to the receptor CD11b/CD18, which causes microglia to release reactive oxygen molecules that are toxic to neurons. Inhibiting fibrinogen binding to the receptor in mice appeared to prevent microglial activation and nerve damage.
“Our imaging work managed to give us a new understanding about the sequence of events in neuroinflammation,” Dr. Akassoglou said. “We were now able to see the whole process as it develops from a healthy brain to full-blown autoimmune disease.”
IDENTIFYING NEW THERAPIES
With the identification of this novel pathway, Dr. Akassoglou began working to identify antibodies and small molecules that could selectively target fibrinogen's pro-inflammatory functions, while leaving its essential role in blood clotting intact. In collaboration with the Small Molecule Discovery Center at UCSF, she and her colleagues have developed assays that use fibrin to activate microglia in vitro, which can be used to identify potential new therapies that selectively target fibrinogen's pro-inflammatory functions. Dr. Akassoglou hopes this research will point the way toward novel treatments for MS and, potentially, for other neurologic diseases.
“There is emerging evidence that fibrinogen and clotting factors are also present in the brain in Alzheimer's disease and traumatic brain injury,” Dr. Akassoglou said. “A hypothesis we're very much interested in exploring is whether this leakage of blood in the brain and activation of the innate immune response is a more common thread in neurologic diseases, and not only limited to MS and autoimmunity.”