Fibrin as an Inhibitor of Remyelination: Mechanisms, Functions, and Therapeutic Applications in Multiple Sclerosis
Abstract
Oligodendrocytes, the myelinating cells of the central nervous system, and their pre-myelinating precursors are thought to be vulnerable targets during inflammatory demyelination. Oligodendrocyte precursors are recruited to sites of myelin disruption, differentiate, and make new myelin sheaths in a process called remyelination, which is critical for overcoming neurological dysfunction. However, several of these precursors are found in chronic MS plaques unable to remyelinate, suggesting failure of these cells to make new myelin. Understanding how remyelination is inhibited in neuroinflammation is critical for achieving repair and protection of neurons. Several lines of evidence suggest that failure to make new myelin is a result of inhibitory environment in the MS brain. Indeed, alteration of the composition of proteins that are deposited in the MS plaques has recently been proposed as an important contributing factor to inhibition of repair. However, which factors in the environment are critical for the inhibition of repair remains poorly understood. A major change in the composition of proteins in the MS plaques is the deposition of the blood protein fibrinogen. In health, fibrinogen is only circulating in the bloodstream and has no access to the brain. However, in MS the blood vessels are damaged and fibrinogen seeps in the brain. We made the unexpected observation that fibrinogen is localized in MS plaques at areas where oligodendrocyte precursors cannot make myelin. Moreover, we showed that fibrinogen inhibits these cells to make myelin in a dish. In this proposal, we will examine how fibrinogen inhibits oligodendrocytes to make new myelin and we will use this information to screen for new drugs that might enhance remyelination in the brain. We expect that results from this proposal will reveal new mechanisms and tools for therapeutic intervention to promote new myelin formation in MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710211
Entities
People
- Katerina Akassoglou
Organizations
- The J. David Gladstone Institutes
- United States Army