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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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References

  1. Wardlaw, J.M. et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 12, 822–838 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Snyder, H.M. et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement. 11, 710–717 (2015).

    Article  PubMed  Google Scholar 

  4. Hachinski, V. & World Stroke Organization. Stroke and potentially preventable dementias proclamation: updated World Stroke Day Proclamation. Stroke J. Cereb. Circ. 46, 3039–3040 (2015).

    Article  Google Scholar 

  5. Phillips, O.R. et al. The superficial white matter in Alzheimer's disease. Hum. Brain Mapp. 37, 1321–1334 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lee, S. et al. White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network. Ann. Neurol. 79, 929–939 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Behrendt, G. et al. Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. Glia 61, 273–286 (2013).

    Article  PubMed  Google Scholar 

  8. Schuff, N. et al. Cerebral blood flow in ischemic vascular dementia and Alzheimer's disease, measured by arterial spin-labeling magnetic resonance imaging. Alzheimers Dement. 5, 454–462 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hanaoka, T. et al. Relationship between white matter lesions and regional cerebral blood flow changes during longitudinal follow up in Alzheimer's disease. Geriatr. Gerontol. Int. 16, 836–842 (2016).

    Article  PubMed  Google Scholar 

  10. Miners, J.S., Schulz, I. & Love, S. Differing associations between Aβ accumulation, hypoperfusion, blood-brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer's disease. J. Cereb. Blood Flow Metab. 38, 103–115 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Arvanitakis, Z., Capuano, A.W., Leurgans, S.E., Bennett, D.A. & Schneider, J.A. Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol. 15, 934–943 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhao, Z., Nelson, A.R., Betsholtz, C. & Zlokovic, B.V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064–1078 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Attwell, D., Mishra, A., Hall, C.N., O'Farrell, F.M. & Dalkara, T. What is a pericyte? J. Cereb. Blood Flow Metab. 36, 451–455 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Sweeney, M.D., Ayyadurai, S. & Zlokovic, B.V. Pericytes of the neurovascular unit: key functions and signaling pathways. Nat. Neurosci. 19, 771–783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Peppiatt, C.M., Howarth, C., Mobbs, P. & Attwell, D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700–704 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hall, C.N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yemisci, M. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031–1037 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Mishra, A. et al. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nat. Neurosci. 19, 1619–1627 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kisler, K. et al. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat. Neurosci. 20, 406–416 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Farkas, E. & Luiten, P.G. Cerebral microvascular pathology in aging and Alzheimer's disease. Prog. Neurobiol. 64, 575–611 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Baloyannis, S.J. & Baloyannis, I.S. The vascular factor in Alzheimer's disease: a study in Golgi technique and electron microscopy. J. Neurol. Sci. 322, 117–121 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Sengillo, J.D. et al. Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease. Brain Pathol. 23, 303–310 (2013).

    Article  PubMed  Google Scholar 

  26. Halliday, M.R. et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J. Cereb. Blood Flow Metab. 36, 216–227. (2016).

    Article  CAS  Google Scholar 

  27. Montagne, A. et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron 85, 296–302 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ghosh, M. et al. Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Ann. Neurol. 78, 887–900 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Tallquist, M.D., French, W.J. & Soriano, P. Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol. 1, E52 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nikolakopoulou, A.M., Zhao, Z., Montagne, A. & Zlokovic, B.V. Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-β signaling. PLoS One 12, e0176225 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Baumann, N. & Pham-Dinh, D. Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol. Rev. 81, 871–927 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Winkler, E.A., Bell, R.D. & Zlokovic, B.V. Pericyte-specific expression of PDGΦβ receptor in mouse models with normal and deficient PDGFβ receptor signaling. Mol. Neurodegener. 5, 32 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bell, R.D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Daianu, M. et al. 7T multi-shell hybrid diffusion imaging (HYDI) for mapping brain connectivity in mice. Proc. SPIE–Int. Soc. Opt. Eng. 9413, 941309 (2015).

    PubMed  PubMed Central  Google Scholar 

  35. Zingg, B. et al. Neural networks of the mouse neocortex. Cell 156, 1096–1111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Potter, G.M. et al. Enlarged perivascular spaces and cerebral small vessel disease. Int. J. Stroke 10, 376–381 (2015).

    Article  PubMed  Google Scholar 

  37. Trapp, B.D. & Nave, K.-A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Pohl, H.B.F. et al. Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. J. Neurosci. 31, 1069–1080 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dewar, D., Underhill, S.M. & Goldberg, M.P. Oligodendrocytes and ischemic brain injury. J. Cereb. Blood Flow Metab. 23, 263–274 (2003).

    Article  PubMed  Google Scholar 

  40. Rosenzweig, S. & Carmichael, S.T. Age-dependent exacerbation of white matter stroke outcomes: a role for oxidative damage and inflammatory mediators. Stroke 44, 2579–2586 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Paul, J., Strickland, S. & Melchor, J.P. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease. J. Exp. Med. 204, 1999–2008 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cortes-Canteli, M. et al. Fibrinogen and β-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease. Neuron 66, 695–709 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Cortes-Canteli, M., Mattei, L., Richards, A.T., Norris, E.H. & Strickland, S. Fibrin deposited in the Alzheimer's disease brain promotes neuronal degeneration. Neurobiol. Aging 36, 608–617 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Schachtrup, C. et al. Fibrinogen inhibits neurite outgrowth via β3-integrin-mediated phosphorylation of the EGF receptor. Proc. Natl. Acad. Sci. USA 104, 11814–11819 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ryu, J.K. et al. Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat. Commun. 6, 8164 (2015).

    Article  PubMed  Google Scholar 

  46. Akassoglou, K., Yu, W.M., Akpinar, P. & Strickland, S. Fibrin inhibits peripheral nerve remyelination by regulating Schwann cell differentiation. Neuron 33, 861–875 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Akassoglou, K. et al. Fibrin depletion decreases inflammation and delays the onset of demyelination in a tumor necrosis factor transgenic mouse model for multiple sclerosis. Proc. Natl. Acad. Sci. USA 101, 6698–6703 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Adams, R.A. et al. The fibrin-derived γ377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J. Exp. Med. 204, 571–582 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Altman, B.J. & Rathmell, J.C. Metabolic stress in autophagy and cell death pathways. Cold Spring Harb. Perspect. Biol. 4, a008763 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. McIlwain, D.R., Berger, T. & Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol. 5, a008656 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Choi, Y.J. et al. Inhibitory effect of mTOR activator MHY1485 on autophagy: suppression of lysosomal fusion. PLoS One 7, e43418 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang, T. et al. Synthesis of improved lysomotropic autophagy inhibitors. J. Med. Chem. 58, 3025–3035 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Schachtrup, C. et al. Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. J. Neurosci. 30, 5843–5854 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sagare, A.P. et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat. Commun. 4, 2932 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. Suh, T.T. et al. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev. 9, 2020–2033 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Shaw, M.A. et al. Plasminogen deficiency delays the onset and protects from demyelination and paralysis in autoimmune neuroinflammatory disease. J. Neurosci. 37, 3776–3788 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wittrup, A. & Lieberman, J. Knocking down disease: a progress report on siRNA therapeutics. Nat. Rev. Genet. 16, 543–552 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De La Fuente, A.G. et al. Pericytes stimulate oligodendrocyte progenitor cell differentiation during CNS remyelination. Cell Rep. 20, 1755–1764 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Takenouchi, T. et al. Novel overgrowth syndrome phenotype due to recurrent de novo PDGFRB mutation. J. Pediatr. 166, 483–486 (2015).

    Article  PubMed  Google Scholar 

  61. Zhao, Z. et al. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat. Neurosci. 18, 978–987 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Basham, M.E. & Seeds, N.W. Plasminogen expression in the neonatal and adult mouse brain. J. Neurochem. 77, 318–325 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Ma, Q. et al. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann. Neurol. 75, 209–219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Barnes, S.R. et al. Optimal acquisition and modeling parameters for accurate assessment of low Ktrans blood-brain barrier permeability using dynamic contrast-enhanced MRI. Magn. Reson. Med. 10.1002/mrm.25793 (2015).

  65. Barnes, S.R. et al. ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies. BMC Med. Imaging 15, 19 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Muir, E.R. et al. Quantitative cerebral blood flow measurements using MRI. Methods Mol. Biol. 1135, 205–211 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Ostergaard, L., Weisskoff, R.M., Chesler, D.A., Gyldensted, C. & Rosen, B.R. High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. Part I: Mathematical approach and statistical analysis. Magn. Reson. Med. 36, 715–725 (1996).

    Article  CAS  PubMed  Google Scholar 

  68. Schalomon, P.M. & Wahlsten, D. Wheel running behavior is impaired by both surgical section and genetic absence of the mouse corpus callosum. Brain Res. Bull. 57, 27–33 (2002).

    Article  PubMed  Google Scholar 

  69. Winkler, E.A. et al. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521–530 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shibata, M. et al. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke J. Cereb. Circ. 38, 2826–2832 (2007).

    Article  Google Scholar 

  71. Fyffe-Maricich, S.L., Schott, A., Karl, M., Krasno, J. & Miller, R.H. Signaling through ERK1/2 controls myelin thickness during myelin repair in the adult central nervous system. J. Neurosci. Off. J. Soc. Neurosci. 33, 18402–18408 (2013).

    Article  CAS  Google Scholar 

  72. Fazekas, F. et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology 43, 1683–1689 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Cizkova, D. et al. Enrichment of rat oligodendrocyte progenitor cells by magnetic cell sorting. J. Neurosci. Methods 184, 88–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Zuchero, J.B. et al. CNS myelin wrapping is driven by actin disassembly. Dev. Cell 34, 152–167 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhu, H. et al. Effect of hypoxia/reoxygenation on cell viability and expression and secretion of neurotrophic factors (NTFs) in primary cultured schwann cells. Anat. Rec. (Hoboken) 2007, 865–870 (2010).

    Article  CAS  Google Scholar 

  76. Gorkun, O.V., Veklich, Y.I., Weisel, J.W. & Lord, S.T. The conversion of fibrinogen to fibrin: recombinant fibrinogen typifies plasma fibrinogen. Blood 89, 4407–4414 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Liu, S. et al. Ancrod and fibrin formation: perspectives on mechanisms of action. Stroke 42, 3277–3280 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lu, Z., Korotcova, L., Murata, A., Ishibashi, N. & Jonas, R.A. Aprotinin, but not ɛ-aminocaproic acid and tranexamic acid, exerts neuroprotection against excitotoxic injury in an in vitro neuronal cell culture model. J. Thorac. Cardiovasc. Surg. 147, 1939–1945 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Liang, Q. et al. Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy. Cell Stem Cell 19, 663–671 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Guo, H. et al. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur. J. Neurosci. 29, 1119–1130 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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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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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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