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

Axel Montagne, Angeliki M. Nikolakopoulou, Zhen Zhao, Abhay P. Sagare, Gabriel Si, Divna Lazic, Samuel R. Barnes, Madelaine Daianu, Anita Ramanathan, Ariel Go, Erica J. Lawson, Yaoming Wang, William J. Mack, Paul M. Thompson, Julie A. Schneider, Jobin Varkey, Ralf Langen, Eric Mullins, Russell E. Jacobs, Berislav V. Zlokovic

Research output: Contribution to journalArticlepeer-review

195 Scopus citations

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.

Original languageEnglish
Pages (from-to)326-337
Number of pages12
JournalNature Medicine
Volume24
Issue number3
DOIs
StatePublished - 1 Mar 2018
Externally publishedYes

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