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

Montagne, Axel and Nikolakopoulou, Angeliki M. and Zhao, Zhen and Sagare, Abhay P. and Si, Gabriel and Lazic, Divna and Barnes, Samuel R. and Daianu, Madelaine and Ramanathan, Anita and Go, Ariel and Lawson, Erica J. and Wang, Yaoming and Mack, William J. and Thompson, Paul M. and Schneider, Julie A. and Varkey, Jobin and Langen, Ralf and Mullins, Eric and Jacobs, Russell E. and Zlokovic, Berislav V. (2018) Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nature Medicine, 24 (3). pp. 326-337. ISSN 1078-8956. https://resolver.caltech.edu/CaltechAUTHORS:20171220-113250861

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/nm.4482DOIArticle
https://www.nature.com/articles/nm.4482PublisherArticle
http://rdcu.be/Gn6FPublisherFree ReadCube access
ORCID:
AuthorORCID
Nikolakopoulou, Angeliki M.0000-0002-1621-4965
Barnes, Samuel R.0000-0002-1065-8442
Jacobs, Russell E.0000-0002-1382-8486
Zlokovic, Berislav V.0000-0002-6802-8232
Alternate Title:Pericyte degeneration causes white matter dysfunction in the mouse CNS
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.
Funders:
Funding AgencyGrant Number
NIHNS100459
NIHAG039452
NIHNS034467
NIHAG023084
Foundation Leducq16 CVD 05
NIHES024936
Issue or Number:3
Record Number:CaltechAUTHORS:20171220-113250861
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171220-113250861
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83982
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:06 Feb 2018 15:31
Last Modified:03 Oct 2019 19:13

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