The Hidden Hand in White Matter: Pericytes and the Puzzle of Demyelination

Disruption of myelin, the fatty sheath-insulating nerve fibers in the white matter, blocks or slows the rapid transmission of electrical signals along nerve cells and contributes to several neurodegenerative diseases such as multiple sclerosis. Traditionally, research has focused on neuronal dysfunction as the primary factor, including autoimmunity, infections, inflammation, and genetic disorders causing demyelination. However, recent insights emphasize the critical role of pericytes, non-neuronal cells that regulate blood flow and maintain the health of blood vessels within white matter. This Perspective explores the principal mechanisms through which pericyte dysfunction contributes to damage and demyelination, including impaired communication with neurons (neurovascular uncoupling), excessive formation of scar tissue (fibrosis), and the infiltration of detrimental substances from the bloodstream. Understanding these mechanisms of pericyte-driven demyelination may lead to the creation of new therapeutic strategies for tackling a range of neurodegenerative conditions.