Pericyte degeneration causes white matter dysfunction in the mouse central nervous system
- Creators
- Montagne, Axel
- Nikolakopoulou, Angeliki M.
- Zhao, Zhen
- Sagare, Abhay P.
- Si, Gabriel
- Lazic, Divna
- Barnes, Samuel R.
- Daianu, Madelaine
- Ramanathan, Anita
- Go, Ariel
- Lawson, Erica J.
- Wang, Yaoming
- Mack, William J.
- Thompson, Paul M.
- Schneider, Julie A.
- Varkey, Jobin
- Langen, Ralf
- Mullins, Eric
- Jacobs, Russell E.
- Zlokovic, Berislav V.
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.
Additional Information
© 2018 Macmillan Publishers Limited, part of Springer Nature. Received: 02 August 2016; Accepted: 04 January 2018; Published online: 05 February 2018. This research was supported by US National Institute of Health grants NS100459, AG039452, NS034467 and AG023084 to B.V.Z., the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no. 16 CVD 05, and ES024936 to W.J.M. The authors thank M.T. Huuskonen for assistance with MRI scanning sessions. Author Contributions: A.M., A.M.N. and Z.Z. designed and performed experiments, analyzed data and contributed to the writing of the paper. A.P.S., G.S., D.L., S.R.B., M.D., A.R., A.G., E.J.L., Y.W., J.V., M.H. and R.L. performed experiments and analyzed data. W.J.M., P.M.T., J.A.S., R.E.J. and E.M. provided guidance for some experiments and edited the paper. B.V.Z. designed all of the experiments and wrote the paper. The authors declare no competing financial interests.Attached Files
Supplemental Material - nm.4482-S1.pdf
Supplemental Material - nm.4482-S2.pdf
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Additional details
- Alternative title
- Pericyte degeneration causes white matter dysfunction in the mouse CNS
- Eprint ID
- 83982
- Resolver ID
- CaltechAUTHORS:20171220-113250861
- NS100459
- NIH
- AG039452
- NIH
- NS034467
- NIH
- AG023084
- NIH
- 16 CVD 05
- Foundation Leducq
- ES024936
- NIH
- Created
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2018-02-06Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field