US scientists have defined for the first time a key underlying process implicated in multiple sclerosis (MS)—a disease that causes progressive and irreversible damage to nerve cells in the brain and spinal cord.
Researchers in the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, have identified in animal models precisely how a protein that seeps from the blood into the brain sets off a response that, over time, causes the nerve cell damage that is a key indicator of MS.
"We have shown that the leakage of blood in the brain acts as an early trigger that sets off the brain's inflammatory response—creating a neurotoxic environment that damages nerve cells,” said Dr Akassoglou
Dr Akassoglou and her team used advanced imaging techniques to monitor the disease's progression in the brain and spinal cord of mice modified to mimic the signs of MS.
The analysis allowed the researchers to study individual cells within the living brain—and to monitor in real-time what happens to these cells as the disease worsens over time.
Fibrinogen, a blood protein that is involved in coagulation, is not found in the healthy brain. In vivo imaging over different stages of disease revealed, however, that a disruption in the blood-brain barrier allows blood proteins—and specifically fibrinogen—to seep into the brain.
Microglia—immune cells that act as the brain's first line of defence—initiate a rapid response to fibrinogen's arrival. They release large amounts of chemically reactive molecules called 'reactive oxygen species.'
This creates a toxic environment within the brain that damages nerve cells and eventually leads to the debilitating symptoms of MS.
Importantly, the team found a strategy to halt this process by genetically modifying fibrinogen in the animal models. This strategy disrupted the protein's interaction with the microglia without affecting fibrinogen's essential role as a blood coagulant..
In these models, the microglia did not react to fibrinogen's arrival and did not create a toxic environment. As a result, the mice failed to show the type of progressive nerve cell damage seen in MS.
"Indeed, targeting the fibrinogen-microglia interactions to halt nerve-cell damage could be a new therapeutic strategy," said Dr. Akassoglou.
The study was recently published in Nature Communications.