Uncovering the hidden role of blood leaks in Alzheimer’s and MS

The question of what causes complex neurological diseases such as Alzheimer’s or multiple sclerosis continues to puzzle scientists and doctors, as the unknown stands in the way of early diagnosis and effective treatments.

Even among identical twins with the same genetic risk factors, one may develop a particular neurological disorder while the other does not.

Because unlike diseases like cystic fibrosis or sickle cell anemia, which are caused by a single gene, most neurological diseases are linked to many – sometimes hundreds – of rare genetic variants. And these variants alone cannot predict who will develop disease, since neurological diseases are also strongly influenced by environmental factors and vascular risks such as high blood pressure, aging, heart disease or obesity.

But there is an often-overlooked thread that connects most neurological diseases, says Katerina Akassoglou, PhD, senior researcher at the Gladstone Institutes: They are characterized by a toxic immune response caused by blood entering the brain through damaged blood vessels.

“Interactions between the brain, blood vessels and immune system are a common thread in the development and progression of many neurological diseases that have traditionally been viewed as very different conditions,” says Akassoglou, senior researcher at the Gladstone Institute of Neurological Diseases and director of the center in Neurovascular Brain Immunology at Gladstone and UC San Francisco.

Now that we know that leaked blood is a key trigger of brain inflammation, we can now look at these diseases from a different perspective.”

Akassoglou, senior researcher, Gladstone Institute of Neurological Diseases

She and her collaborators share their insights on this topic in a commentary article published in cell 50th anniversary edition “Focus on Neuroscience”.

Neutralize the perpetrator

Akassoglou and her lab have long studied how blood entering the brain triggers neurological diseases, essentially 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, which is normally involved in blood clotting – is responsible for triggering this harmful cascade. The process has been observed in diseases as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, preterm birth and even COVID-19. However, Akassoglou and her 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 in animal models.

“As a first step, we know that neutralizing fibrin reduces the burden of vascular dysfunction,” says Akassoglou. Regardless of what originally caused the blood leaks, be it a head injury, an autoimmune disease, genetic mutations, amyloid in the brain, or an infection, neutralizing fibrin appears to be protective against disease in several animal models.

The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets the inflammatory properties of fibrin without interfering with its essential role in blood clotting. This fibrin-targeting immunotherapy has been shown in mice to protect against multiple sclerosis and Alzheimer’s disease and to treat the neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety trials by Therini Bio, a biotech company founded to advance discoveries from Akassoglou’s lab.

A new era of brain research

In the cell In their commentary, Akassoglou and her colleagues argue that seemingly different neurological diseases need to 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 between academia, industry and foundations, will drive innovation in drug discovery and transform medical practice for neurological diseases.

“This is a new opportunity for drug discovery that goes beyond treating genes or environmental factors alone,” says Akassoglou. “To usher in this new era, we must leverage new technologies and adopt an interdisciplinary approach that takes into account the important role of immune and vascular systems in neurodegeneration.”