Pericyte Degeneration Causes White Matter Dysfunction in the Mouse Central Nervous System

Nat Med. 2018 Mar;24(3):326-337. doi: 10.1038/nm.4482. Epub 2018 Feb 5.

Abstract

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, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted 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, our data indicate that 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / pathology
  • Blood Vessels / diagnostic imaging
  • Blood Vessels / pathology
  • Blood-Brain Barrier / pathology
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Brain / physiopathology
  • Central Nervous System / blood supply
  • Central Nervous System / diagnostic imaging
  • Central Nervous System / physiopathology*
  • Dementia / blood
  • Dementia / diagnostic imaging
  • Dementia / physiopathology*
  • Humans
  • Leukoencephalopathies / blood
  • Leukoencephalopathies / diagnostic imaging
  • Leukoencephalopathies / physiopathology*
  • Magnetic Resonance Imaging
  • Mice
  • Microcirculation
  • Myelin Sheath / metabolism
  • Pericytes / metabolism
  • Pericytes / pathology
  • White Matter / blood supply
  • White Matter / diagnostic imaging
  • White Matter / physiopathology*