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RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

Nature Medicine volume 24, pages 326–337 (2018)Cite this article

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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.

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Figure 1: White-matter microvascular changes in AD and pericyte-deficient mice.
Figure 2: White-matter structural changes and loss of connectivity in pericyte-deficient mice.
Figure 3: White-matter-related functional deficits in pericyte-deficient mice.
Figure 4: Pericyte-deficient mice develop an early axon degeneration and loss of myelin.
Figure 5: Loss of mature oligodendrocytes in pericyte-deficient mice and fibrinogen and fibrin toxicity to mouse oligodendrocytes.
Figure 6: White-matter changes in pericyte-deficient mice after pharmacological or genetic manipulations of systemic fibrinogen levels.

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Acknowledgements

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.

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Author notes

  1. Axel Montagne, Angeliki M Nikolakopoulou and Zhen Zhao: These authors contributed equally to this work.

Authors and Affiliations

  1. Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Axel Montagne, Angeliki M Nikolakopoulou, Zhen Zhao, Abhay P Sagare, Gabriel Si, Divna Lazic, Anita Ramanathan, Ariel Go, Erica J Lawson, Yaoming Wang, Jobin Varkey, Ralf Langen, Russell E Jacobs & Berislav V Zlokovic

  2. Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    Axel Montagne, Angeliki M Nikolakopoulou, Zhen Zhao, Abhay P Sagare, Divna Lazic, Anita Ramanathan, Erica J Lawson, Yaoming Wang, Jobin Varkey, Ralf Langen, Russell E Jacobs & Berislav V Zlokovic

  3. Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia

    Divna Lazic

  4. Biological Imaging Center, Beckman Institute, California Institute of Technology, Pasadena, California, USA

    Samuel R Barnes & Russell E Jacobs

  5. Imaging Genetics Center, Mark & Mary Stevens Neuroimaging & Informatics Institute, University of Southern California, Marina del Rey, California, USA

    Madelaine Daianu & Paul M Thompson

  6. Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

    William J Mack

  7. Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA

    Julie A Schneider

  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

    Eric Mullins

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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.

Corresponding author

Correspondence to Berislav V Zlokovic.

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The authors declare no competing financial interests.

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This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1038/s41591-024-02935-6

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Montagne, A., Nikolakopoulou, A., Zhao, Z. et al. RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 24, 326–337 (2018). https://doi.org/10.1038/nm.4482

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