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

Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.

Author information

1
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
2
Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
3
Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia.
4
Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, USA.
5
Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, University of Southern California, Marina del Rey, California, USA.
6
Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
7
Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
8
Division of Hematology and Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.

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.

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