A new study finds that when a blood protein crosses the blood-brain barrier, it can inhibit the brain’s ability to effect remyelination.
Katerina Akassoglou, PhD
New research suggests a protein in the blood is to blame for central nervous system (CNS) dysfunction that prevents remyelination in patients with multiple sclerosis (MS).
The study, by researchers at the California-based Gladstone Institutes, identifies the blood-clotting protein fibrinogen as the source of the central nervous system’s inability to produce myelin. The data open up new possible therapeutic strategies and could have broad implications for the multiple sclerosis (MS) community.
The new insights also help tie together previously known information about the central nervous system (CNS) in patients with MS. For instance, it was already known that disruption in the blood-brain barrier can cause blood proteins to leak into the CNS. And previous research has indicated that fibrinogen specifically is present in the brain at various stages of MS, including prior to demyelination. Finally, Gladstone Institutes researchers had earlier discovered that fibrinogen can cause potentially damaging inflammation in the brain.
Gladstone Senior Investigator Katerina Akassoglou, PhD, a Professor of Neurology at the University of California, San Francisco, led the research teams that looked into fibrinogen and inflammation, as well as the new study on remyelination. Her research focuses on the blood-brain barrier and fibrinogen.
She said the new study was designed to answer the question of whether blood-derived molecules were extrinsic inhibitors of remyelination. In the new study, Akassoglou and colleagues report that fibrinogen does in fact prevent remyelination, by stopping adult stem cells from maturing into myelin-producing cells. That finding has implications across the spectrum of MS patients, Akassoglou told MD Magazine.
“Overall, studies from multiple laboratories using a large number of tissue data banks for MS patients have demonstrated that fibrinogen is present broadly in MS patients,” Akassoglou said. “Therefore, one would expect that if we could stop the toxic effects of fibrinogen, there would be a broad impact for the MS community.”
Just how to stop those toxic effects is another question, and a complicated one. Akassoglou said most anticoagulant treatments that block fibrin formation “do not deplete fibrinogen and also have adverse hemorrhagic effects.”
There’s some momentum behind efforts to strengthen the blood-brain barrier to prevent the leakage of proteins like fibrinogen, Akassoglou said, but that won’t fully solve the problem because such a treatment wouldn’t eliminate the fibrinogen that had already made it into the brain.
Akassoglou said the better option would be to develop therapies that neutralize CNS-trapped fibrinogen without negatively impacting hemostasis.
“In our prior studies, we developed a fibrin peptide that can selectively inhibit the damaging functions of fibrin in brain inflammation, without affecting its beneficial role in hemostasis,” Akassoglou said. “We showed that intranasal administration of the fibrin peptide can suppress EAE (the mouse model for MS). We are currently working on developing tools to selectively neutralize the inhibitory effects of fibrinogen in brain repair.”
The success of that research could impact other CNS diseases, such as stroke, neonatal diseases, and potentially Alzheimer’s disease.
The study, “Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage," was published online in the journal Neuron this month.