Pericyte degeneration causes white matter dysfunction in the mouse CNS

Diffuse white matter disease associated with small vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, behavior and tissue analysis, here we show that pericyte degeneration disrupts white matter microcirculation causing accumulation of toxic blood-derived fibrin(ogen) deposits and blood flow reductions, which triggers loss of myelin, axons and oligodendrocytes. This disrupts brain circuits leading to white matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white matter changes. Thus, pericytes control white matter structure and function, which has implications for the pathogenesis and treatment of human white matter disease associated with small vessel disease.