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

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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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.

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Correspondence to Berislav V Zlokovic.

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The authors declare no competing financial interests.

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Montagne, A., Nikolakopoulou, A., Zhao, Z. et al. 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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