Inhibiting Blood to Save the Brain

Description
Researchers at the UCSD School of Medicine have identified a fibrin-
derived peptide that inhibits this specific inflammation process in 
mouse models of MS, reducing MS symptoms.

Newswise — A fibrous protein called fibrinogen, found in circulating 
blood and important in blood clotting, can promote multiple sclerosis 
(MS) when it leaks from the blood into the brain, triggering 
inflammation that leads to MS-related nerve damage. Researchers at 
the University of California, San Diego (UCSD) School of Medicine 
have identified a fibrin-derived peptide that inhibits this specific 
inflammation process in mouse models of MS, reducing MS symptoms.

“Current strategies to develop therapies to fight MS primarily target 
T cells,” said Katerina Akassoglou, Ph.D., assistant professor in 
UCSD’s Department of Pharmacology, whose study was published in the 
March 19 issue of Journal of Experimental Medicine. “Blood proteins 
have been neglected as a therapeutic target, but this research shows 
that a blood clotting factor is an important player in MS.”

MS is an inflammatory disease that affects the central nervous 
system, causing symptoms such as loss of balance and muscle 
coordination, and changes in cognitive function. The disease is 
marked by loss of myelin, a material that coats nerve fibers. Past 
studies showed that the destruction of the myelin sheath is 
associated with the accumulation of fibrinogen deposits in the brain 
of human MS patients. In this study, Akassoglou and colleagues showed 
that fibrinogen is not merely associated with the damage in MS, but 
an active participant. Fibrinogen activates macrophage cells in the 
brain called microglia, causing inflammation which damages myelin.

The scientists sought to design a therapeutic strategy that would 
block the damaging effects of fibrinogen without affecting its 
beneficial blood coagulation. Studying a mouse model, the researchers 
identified a specific receptor called Mac-1 that is expressed by 
microglial cells and binds to fibrinogen. Mice expressing a mutant 
form of fibrinogen that failed to bind Mac-1 had fewer inflammatory 
lesions and less severe MS symptoms. Blocking the interaction between 
Mac-1 and fibrinogen after the first episode of paralysis using the 
fibrin peptide prevented subsequent relapses. It also prevented 
further microglia activation and damage to myelin in the diseased 
mice, allowing them to survive with improved motor function.

“Importantly, this approach blocks fibrin’s interaction with 
microglia, but not with platelets, so clotting wouldn’t be impacted,” 
said Akassoglou, adding that this potential MS therapy might also 
have applications to other blood-brain barrier diseases where blood 
leakage and microglia activation is present such as spinal cord 
injury, Alzheimer’s disease or stroke.

Additional contributors to the paper include Ryan A. Adams, Shoana L. 
Sikorski and Tal Nuriel of UCSD’s Department of Pharmacology; Jan 
Bauer and Hans Lassmann, Center for Brain Research, Medical 
University of Vienna; and Matthew J. Flick and Jay L. Degen, 
Children’s Hospital Research Foundation and University of Cincinnati 
College of Medicine.

Funding for the study was provided in part by the National Institute 
for Neurological Disorders and Stroke, part of the National 
Institutes of Health, and by the National Multiple Sclerosis Society.