Neuroscientist Katerina Akassoglou, PhD, is calling for a fundamental change in the way scientists approach neurological disorders.
Traditionally, these diseases have been classified into distinct categories: neurodegenerative (e.g., Alzheimer’s), inflammatory (e.g., multiple sclerosis), and vascular (e.g., stroke). But recent insights, including research from Akassoglou’s lab at the Gladstone Institutes, have led to a reassessment of the complex relationships between the brain, immune, and vascular systems and their roles in disease.
“We need to reevaluate our understanding of the causes and signals that regulate disease onset and progression, and recognize that neurological disorders cannot be described in isolation,” Akassoglou said.
Akassoglou’s mission stems from the fact that, despite scientists’ best efforts, effective therapies for many important neurological diseases are lacking. She believes that taking a more integrated approach to studying these conditions will lead to new insights about the brain and a better way to categorize and treat its diseases. With neurological disorders striking an estimated 50 million Americans each year, the potential impact of this work is tremendous.
“We must look at the common threads among diseases with similar neurovascular and immune abnormalities to understand their underlying complexities,” she continued. “This perspective will offer us a window into new therapeutic targets for these diseases.”
Tackling the Challenges of Multiple Sclerosis
Akassoglou became interested in the convergence of these systems through her research on multiple sclerosis (MS).
An autoimmune disease, MS is an unpredictable and potentially debilitating disorder of the central nervous system that affects more than two million people worldwide. It is very difficult to manage and can advance from the more benign relapsing-remitting form of the disease to an aggressively progressive one. There is no cure for MS and no effective treatments for the more severe form. Adding to the frustration for clinicians and their patients is the fact that there is no way to predict which patients will deteriorate and when.
Akassoglou addressed these challenges by trying to understand what initially triggers the brain’s autoimmune response. However, instead of concentrating on the neurons themselves, she focuses her research on the network surrounding and supporting the cells: the brain’s vascular and immune system.
Clues in the Blood
Research has shown that errant blood-clotting factors are present in the brains of patients with MS. The presence of these substances in the brain indicates a disruption of the blood-brain barrier (BBB), which separates the brain from the circulatory system, filtering out most blood-borne molecules and protecting the brain from pathogens.
“We investigate how the influx of blood proteins into the brain contributes to disease progression and neurological dysfunction,” Akassoglou said.
Research in her lab showed that when proteins important for normal blood clotting enter the brain, they trigger harmful inflammation and neuronal damage. She discovered that one protein in particular, fibrinogen, is abundant in the brains of patients with MS and may be to blame for the development of autoimmunity.
“We identified fibrinogen as the key protein in the blood that binds to brain cells and induces inflammation, neuron damage, and scar formation,” Akassoglou explained. “We think it may be a valuable biomarker to diagnose and track disease progression, and a new target to develop drugs for MS.”
When the BBB is disrupted, fibrinogen leaks into the brain and forms deposits that activate microglia, the brain’s immune cells. The microglia then “summon” peripheral immune cells from other parts of the body, and these cells proceed to attack the protective myelin sheaths that surround the axons—or nerve fibers—in the brain.
A Common Thread
Fibrinogen is an important blood protein that promotes autoimmunity and demyelination, the major causal drivers of MS. However, fibrinogen is also present in the brain in other neurological conditions, including Alzheimer’s disease, other dementias, stroke, and traumatic brain injury. This finding suggests that BBB breach and fibrinogen leakage occurs in these disorders as well.
“We don’t yet know if BBB disruption is a cause or a consequence of neurological disease. It’s a classic ‘chicken-or-egg’ question,” Akassoglou said. “But we do know that disruption occurs, and the blood proteins we have found in the brain are able to activate the brain’s immune cells and damage neurons.”
Akassoglou’s laboratory uses mouse models of blood-driven neural inflammation and autoimmunity to explore further the role of fibrinogen in MS, and she is now pursuing similar lines of investigation on other neurological diseases.
“This work will help us understand the mechanisms that may contribute to a host of conditions associated with BBB disruption, activation of the brain’s immune system, and neurodegeneration,” she said.
Recognizing that fibrinogen can kick-start the chain reaction that leads to inflammation and myelin damage, Akassoglou and her team are now looking at ways to target the harmful activities of the protein in the brain without affecting its function in the blood.
“We don’t want to block fibrinogen completely, since it plays an important role in blood clotting,” she said. “Fortunately, we have developed strategies that will allow us to maintain that part of its function while removing the pathogenic effects. If this shows promise, our work could eventually produce a drug to treat patients with fibrinogen deposits in their brains.”
Akassoglou also thinks fibrinogen and other blood clotting proteins could serve as a biomarker for MS. A biomarker is a measurable indicator of the presence or severity of a disease, enabling physicians and researchers to track disease progression. An effective biomarker could transform diagnosis and care of MS by more easily categorizing patients into different subsets that may differ in regards to disease progression or response to therapies. It would also aid in the development of new treatments and improve clinical trials.
On the Horizon
Akassoglou’s ground-breaking work on blood proteins advances a key objective—to develop novel treatments for neurological diseases. To this end, she continues research to understand how blood proteins harm the brain and to develop new therapies that target these proteins. She is also collaborating with colleagues at the University of California, San Francisco to study these proteins in MS patients over a 10-year period.
“Our research on BBB disruption and the role certain proteins play in neuro-inflammation has advanced our efforts to explore unexpected culprits in neurological diseases,” Akassoglou said. “My hope is that the progress we’ve made on multiple sclerosis in the laboratory will one day lead to improvements in prevention, diagnosis, and treatment of all neurological diseases that involve blood clotting proteins in the brain.”