A collective of researchers believes it’s time for a fresh perspective on how we understand and manage complex disorders like Alzheimer’s and multiple sclerosis.
The fundamental causes of intricate neurological disorders such as Alzheimer’s and multiple sclerosis remain a major challenge for scientists and healthcare professionals, with these unknown elements hindering early diagnosis and effective treatment options.
Interestingly, even in identical twins who have identical genetic predispositions, one may go on to develop a neurological condition while the other might not.
This discrepancy occurs because, unlike single-gene disorders such as cystic fibrosis or sickle-cell anemia, most neurological illnesses are influenced by multiple rare genetic variations—sometimes numbering in the hundreds. These genetic factors alone aren’t sufficient to predict disease development, as environmental influences and vascular risks—including high blood pressure, aging, heart conditions, or obesity—also play a significant role.
However, Katerina Akassoglou, PhD, a senior researcher at the Gladstone Institutes, highlights a common but often overlooked factor that links many neurological conditions: a harmful immune response triggered by blood leakage into the brain through compromised blood vessels.
“The relationship between the brain, blood vessels, and the immune system is a shared element in the emergence and progression of various neurological diseases that have typically been regarded as distinct,” explains Akassoglou, who is a senior investigator with the Gladstone Institute of Neurological Diseases and heads the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. “Recognizing that blood leakage significantly contributes to brain inflammation allows us to rethink our approach to these diseases.”
Her and her team’s observations are detailed in a commentary piece featured in Cell’s 50th anniversary “Focus on Neuroscience” issue.
Neutralizing the Culprit
Akassoglou and her research team have long examined how blood that seeps into the brain can lead to neurological disorders by disrupting the brain’s immune responses, which initiates a harmful and often irreversible chain reaction causing neuronal damage.
A specific blood protein known as fibrin, which is typically involved in clotting, is a major contributor to this damaging process. This phenomenon has been observed in a variety of conditions, including Alzheimer’s, traumatic brain injuries, multiple sclerosis, premature births, and even COVID-19. However, Akassoglou and her team discovered that this detrimental process could be halted or mitigated by “neutralizing” fibrin to deactivate its harmful properties—an approach that appears to offer protection against numerous neurological diseases in animal studies.
“The initial step shows that neutralizing fibrin alleviates the complications of vascular dysfunction,” states Akassoglou. Regardless of the initial cause of blood leakage—whether due to injuries, autoimmunity, genetic anomalies, amyloid deposits, or infections—neutralizing fibrin seems to provide protective benefits across various animal disease models.
The researchers previously developed a therapeutic monoclonal antibody that specifically targets the inflammatory effects of fibrin while preserving its crucial role in blood coagulation. This fibrin-targeting immunotherapy has demonstrated protective properties in mice against multiple sclerosis and Alzheimer’s phenomena and aids in mitigating neurological symptoms of COVID-19. A humanized version of this groundbreaking fibrin immunotherapy is currently undergoing Phase 1 safety clinical trials by Therini Bio, a biotech firm established to advance discoveries made in Akassoglou’s lab.
A New Era of Brain Research
In their Cell commentary, Akassoglou and her colleagues advocate that seemingly unrelated neurological disorders need to be reevaluated in light of new insights related to the interplay among blood, brain, and immune systems.
They suggest that, over the next decade, scientific innovations will arise from collaborations involving immunologists, neuroscientists, hematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These alliances—developed across academia, industry, and funding organizations—will drive progress in drug discovery and revolutionize medical practices concerning neurological conditions.
“This is a fresh opportunity for drug discovery that embraces not just genetic factors or environmental influences on their own,” asserts Akassoglou. “To enter this new phase, we must utilize modern technologies and adopt an interdisciplinary approach that recognizes the crucial roles of immune and vascular systems in neurodegenerative processes.”
