Blood-brain-immune interface and neurodegenerative disorders
The question of what causes complex neurological diseases such as Alzheimer’s or multiple sclerosis continues to confound scientists and doctors, with the unknowns standing in the way of early diagnoses and effective treatments.
Even among identical twins who share the same genetic risk factors, one may develop a particular neurological disease while the other does not.
That’s because unlike diseases such as cystic fibrosis or sickle-cell anemia, which are caused by a single gene, most neurological disorders are associated with many—sometimes hundreds—of rare genetic variants. And on their own, these variants can’t predict who will develop disease, as neurological conditions are also strongly influenced by environmental factors and vascular risks such as high blood pressure, aging, heart disease, or obesity.
But there’s one often-overlooked thread that connects most neurological diseases, says a senior investigator. They’re marked by a toxic immune reaction caused by blood that leaks into the brain through damaged blood vessels.
“Interactions between the brain, blood vessels, and the immune system are a common thread in the development and progression of many neurological diseases that have been traditionally viewed as very different conditions,” says a senior investigator. “Knowing that leaked blood is a key driver of brain inflammation, we can now approach these diseases from a different angle.”
The researchers share their insights on this topic in a commentary article published in Cell’s 50th anniversary “Focus on Neuroscience” issue.
The lab have long investigated how blood that leaks into the brain trigger neurologic diseases, essentially by hijacking the brain’s immune system and setting off a cascade of harmful often-irreversible effects that result in damaged neurons.
One blood protein in particular—fibrin, normally involved in blood coagulation—is responsible for setting off this detrimental cascade. The process has been observed in conditions as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, premature birth, and even COVID-19. However, the team found that the process could be prevented or interrupted by “neutralizing” fibrin to deactivate its toxic properties—an approach that appears to protect against many neurological diseases when tested in animal models.
“As a first step, we know that neutralizing fibrin reduces the burden posed by vascular dysfunction,” the author says. Regardless of what initially caused the blood leaks, be it a head injury, autoimmunity, genetic mutations, brain amyloid or infection, neutralizing fibrin appears to be protective in multiple animal models of disease.
The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. This fibrin-targeting immunotherapy has shown, in mice, to protect from multiple sclerosis and Alzheimer’s, and to treat neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio, a biotech company launched to advance discoveries from the lab.
In the Cell commentary, the authors make the case that seemingly disparate neurological diseases must be viewed differently in light of new research on the blood-brain-immune interface.
They say that in the coming decade, scientific breakthroughs will emerge from collaborative networks of immunologists, neuroscientists, hematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These partnerships—forged across academia, industry, and foundations—will catalyze innovation in drug discovery and transform medical practice for neurological diseases.
“This is a new opportunity for drug discovery that goes beyond addressing genes alone or environmental factors alone,” the senior investigator says. “To usher in this new era, we must leverage new technologies and embrace an interdisciplinary approach that accounts for the important roles of immune and vascular systems in neurodegeneration.”
https://www.cell.com/cell/fulltext/S0092-8674(24)01037-7
