Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics

Abstract

The blood coagulation protein fibrinogen is deposited in the brain in a wide range of neurological diseases and traumatic injuries with blood–brain barrier (BBB) disruption. Recent research has uncovered pleiotropic roles for fibrinogen in the activation of CNS inflammation, induction of scar formation in the brain, promotion of cognitive decline and inhibition of repair. Such diverse roles are possible in part because of the unique structure of fibrinogen, which contains multiple binding sites for cellular receptors and proteins expressed in the nervous system. The cellular and molecular mechanisms underlying the actions of fibrinogen are beginning to be elucidated, providing insight into its involvement in neurological diseases, such as multiple sclerosis, Alzheimer disease and traumatic CNS injury. Selective drug targeting to suppress the damaging functions of fibrinogen in the nervous system without affecting its beneficial effects in haemostasis opens a new fibrinogen therapeutics pipeline for neurological disease.

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Figure 1: Fibrinogen at the nexus of the brain–vascular–immune axis.
Figure 2: Fibrinogen structure, cellular targets and signalling networks in the nervous system.
Figure 3: Timeline of in vivo genetic and pharmacological evidence showing a causal role for fibrin and/or fibrinogen in the development of neurological disease.
Figure 4: Fibrinogen at the helm of CNS innate immune activation and neurodegeneration.
Figure 5: The coagulation cascade and its final product fibrin as clinically relevant biomarkers and potential therapeutic targets for neurological disease.

References

  1. 1

    Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Vemuri, P. et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761–771 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Adams, R. A., Schachtrup, C., Davalos, D., Tsigelny, I. & Akassoglou, K. Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis. Curr. Med. Chem. 14, 2925–2936 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Davalos, D. & Akassoglou, K. Fibrinogen as a key regulator of inflammation in disease. Semin. Immunopathol. 34, 43–62 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Adams, R. A. et al. The fibrin-derived γ77-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J. Exp. Med. 204, 571–582 (2007). This study provides genetic and pharmacological evidence that inhibition of the fibrin–CD11b/CD18 interaction attenuates neuroinflammation without an adverse effect in blood coagulation.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Davalos, D. et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat. Commun. 3, 1227 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    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). This study shows that fibrin depletion protects from cognitive impairment in AD mice.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Akassoglou, K., Yu, W. M., Akpinar, P. & Strickland, S. Fibrin inhibits peripheral nerve remyelination by regulating Schwann cell differentiation. Neuron 33, 861–875 (2002). This study used fibrinogen-deficient mice to test causality in nervous system pathogenesis and showed that fibrinogen can alter functions of glial cells.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Liebner, S., Czupalla, C. J. & Wolburg, H. Current concepts of blood-brain barrier development. Int. J. Dev. Biol. 55, 467–476 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15

    Iadecola, C. The Neurovascular Unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Knowland, D. et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82, 603–617 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Baeten, K. M. & Akassoglou, K. Extracellular matrix and matrix receptors in blood–brain barrier formation and stroke. Dev. Neurobiol. 71, 1018–1039 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Thomas, W. S. et al. Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke 24, 847–853 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22

    Akassoglou, K. & Strickland, S. Nervous system pathology: the fibrin perspective. Biol. Chem. 383, 37–45 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Adams, R. A., Passino, M., Sachs, B. D., Nuriel, T. & Akassoglou, K. Fibrin mechanisms and functions in nervous system pathology. Mol. Interv 4, 163–176 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Drouin-Ouellet, J. et al. Cerebrovascular and blood-brain barrier impairments in Huntington's disease: potential implications for its pathophysiology. Ann. Neurol. 78, 160–177 (2015).

    Article  Google Scholar 

  26. 26

    Tennent, G. A. et al. Human plasma fibrinogen is synthesized in the liver. Blood 109, 1971–1974 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Weisel, J. W. Fibrinogen and fibrin. Adv. Protein Chem. 70, 247–299 (2005).

    CAS  Article  Google Scholar 

  28. 28

    Lord, S. T. Molecular mechanisms affecting fibrin structure and stability. Arterioscler Thromb. Vasc. Biol. 31, 494–499 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Mosesson, M. W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 3, 1894–1904 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Yang, Z., Mochalkin, I. & Doolittle, R. F. A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides. Proc. Natl Acad. Sci. USA 97, 14156–14161 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Holmback, K., Danton, M., Suh, T., Daugherty, C. & Degen, J. Impaired platelet aggregation and sustained bleeding in mice lacking the fibrinogen motif bound by integrin αIIb β3. EMBO J. 15, 5760–5771 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Rooney, M. M., Parise, L. V. & Lord, S. T. Dissecting clot retraction and platelet aggregation. Clot retraction does not require an intact fibrinogen γ chain C terminus. J. Biol. Chem. 271, 8553–8555 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Castellino, F. J. & Ploplis, V. A. Structure and function of the plasminogen/plasmin system. Thromb. Haemost. 93, 647–654 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Bardehle, S., Rafalski, V. A. & Akassoglou, K. Breaking boundaries-coagulation and fibrinolysis at the neuro-vascular interface. Front. Cell Neurosci. 9, 354 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Osterwalder, T. et al. The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin. J. Biol. Chem. 273, 2312–2321 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Sachs, B. D. et al. p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J. Cell Biol. 177, 1119–1132 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Laurens, N., Koolwijk, P. & de Maat, M. P. Fibrin structure and wound healing. J. Thromb. Haemost. 4, 932–939 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Chan, J. C., Duszczyszyn, D. A., Castellino, F. J. & Ploplis, V. A. Accelerated skin wound healing in plasminogen activator inhibitor-1-deficient mice. Am. J. Pathol. 159, 1681–1688 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Bugge, T. H. et al. Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 87, 709–719 (1996). This paper provides genetic evidence that fibrin is the major substrate for plasmin and demonstrates that impaired fibrin degradation is a driver of multi-organ pathology and impaired wound healing.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Romer, J. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat. Med. 2, 287–292 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Motley, M. P. et al. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood 127, 1085–1096 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Doolittle, R. F. A detailed consideration of a principal domain of vertebrate fibrinogen and its relatives. Protein Sci. 1, 1563–1577 (1992).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Doolittle, R. F., McNamara, K. & Lin, K. Correlating structure and function during the evolution of fibrinogen-related domains. Protein Sci. 21, 1808–1823 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Matsushita, M. et al. A novel human serum lectin with collagen- and fibrinogen-like domains that functions as an opsonin. J. Biol. Chem. 271, 2448–2454 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Marazzi, S. et al. Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes. J. Immunol. 161, 138–147 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Chiquet-Ehrismann, R. & Tucker, R. P. Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol. 3, a004960 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Hanington, P. C. & Zhang, S. M. The primary role of fibrinogen-related proteins in invertebrates is defense, not coagulation. J. Innate Immun. 3, 17–27 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Powell, P. A., Wesley, C., Spencer, S. & Cagan, R. L. Scabrous complexes with Notch to mediate boundary formation. Nature 409, 626–630 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Lassmann, H. Multiple sclerosis pathology: evolution of pathogenetic concepts. Brain Pathol. 15, 217–222 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Lassmann, H., Bruck, W. & Lucchinetti, C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol. Med. 7, 115–121 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Lucchinetti, C. F., Brueck, W., Rodriguez, M. & Lassmann, H. Multiple sclerosis: lessons from neuropathology. Semin. Neurol. 18, 337–349 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Rindficisch, E. Histologisches detail zu der grauen degeneration von gehirn und ruckenmark. Arch. Pathol. Anat. Physiol. 26, 474–483 (1863).

    Article  Google Scholar 

  53. 53

    Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169–180 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Grossman, R. I. et al. Multiple sclerosis: serial study of gadolinium-enhanced MR imaging. Radiology 169, 117–122 (1988).

    CAS  Article  Google Scholar 

  55. 55

    Miller, D. H. et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 111, 927–939 (1988).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Kermode, A. G. et al. Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 113, 1477–1489 (1990).

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Cotton, F., Weiner, H. L., Jolesz, F. A. & Guttmann, C. R. MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals. Neurology 60, 640–646 (2003).

    Article  Google Scholar 

  58. 58

    Gaitan, M. I., Sati, P., Inati, S. J. & Reich, D. S. Initial investigation of the blood-brain barrier in MS lesions at 7 tesla. Mult. Scler. 19, 1068–1073 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Gaitan, M. I. et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann. Neurol. 70, 22–29 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Bruck, W. et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann. Neurol. 42, 783–793 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Katz, D. et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann. Neurol. 34, 661–669 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Vos, C. M. et al. Blood-brain barrier alterations in both focal and diffuse abnormalities on postmortem MRI in multiple sclerosis. Neurobiol. Dis. 20, 953–960 (2005).

    CAS  Article  Google Scholar 

  63. 63

    Kirk, J., Plumb, J., Mirakhur, M. & McQuaid, S. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J. Pathol. 201, 319–327 (2003).

    Article  Google Scholar 

  64. 64

    Kwon, E. E. & Prineas, J. W. Blood-brain barrier abnormalities in longstanding multiple sclerosis lesions. An immunohistochemical study. J. Neuropathol. Exp. Neurol. 53, 625–636 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Han, M. H. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076–1081 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Yates, R. L. et al. Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann. Neurol. 82, 259–270 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67

    Gveric, D. et al. Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage. Brain 124, 1978–1988 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Gveric, D., H. B., Petzold, A., Lawrence, D. A. & Cuzner, M. L. Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors. Brain 126, 1–9 (2003).

    Article  Google Scholar 

  69. 69

    Marik, C., Felts, P. A., Bauer, J., Lassmann, H. & Smith, K. J. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130, 2800–2815 (2007). This study demonstrates that fibrin deposition and microglial activation are early events in MS pathology and precede demyelination.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Gay, F. W., Drye, T. J., Dick, G. W. & Esiri, M. M. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterization of the primary demyelinating lesion. Brain 120, 1461–1483 (1997).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    Wakefield, A. J., More, L. J., Difford, J. & McLaughlin, J. E. Immunohistochemical study of vascular injury in acute multiple sclerosis. J. Clin. Pathol. 47, 129–133 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. 72

    Adams, R. D. & Kubik, C. S. The morbid anatomy of the demyelinative disease. Am. J. Med. 12, 510–546 (1952).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).

    Article  Google Scholar 

  74. 74

    Maggi, P. et al. The formation of inflammatory demyelinated lesions in cerebral white matter. Ann. Neurol. 76, 594–608 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75

    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  PubMed Central  Google Scholar 

  76. 76

    Ugarova, T. P. et al. Sequence γ377-395(P2), but not γ190-202(P1), is the binding site for the αMI-domain of integrin αMβ2 in the γC-domain of fibrinogen. Biochemistry 42, 9365–9373 (2003). This paper shows that the major binding site for the CD11b/CD18 integrin is the P2 epitope (sequence 377–395) in the γC-domain of fibrinogen, which is exposed after cleavage of fibrinogen to insoluble fibrin.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Lishko, V. K., Kudryk, B., Yakubenko, V. P., Yee, V. C. & Ugarova, T. P. Regulated unmasking of the cryptic binding site for integrin αMβ2 in the γC-domain of fibrinogen. Biochemistry 41, 12942–12951 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Smiley, S. T., King, J. A. & Hancock, W. W. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J. Immunol. 167, 2887–2894 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    Millien, V. O. et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341, 792–796 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    Perera, P. Y. et al. CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J. Immunol. 166, 574–581 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    Ling, G. S. et al. Integrin CD11b positively regulates TLR4-induced signalling pathways in dendritic cells but not in macrophages. Nat. Commun. 5, 3039 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Noubir, S., Hmama, Z. & Reiner, N. E. Dual receptors and distinct pathways mediate interleukin-1 receptor-associated kinase degradation in response to lipopolysaccharide. Involvement of CD14/TLR4, CR3, and phosphatidylinositol 3-kinase. J. Biol. Chem. 279, 25189–25195 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Hanspers, K., Akassoglou, K. & Mendiola, A. S. Fibrin complement receptor 3 signaling pathway (Homo sapiens). Wikipathways.org/Index.php/Pathway:WP4136 (2017).

  85. 85

    Paterson, P. Y. Experimental allergic encephalomyelitis: role of fibrin deposition in immunopathogenesis of inflammation in rats. Fed. Proc. 35, 2428–2434 (1976). This study provides evidence that depletion of fibrin by the defibrinogenating agent ancrod suppresses EAE.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    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).

    CAS  Article  Google Scholar 

  87. 87

    Yang, Y., Tian, S. J., Wu, L., Huang, D. H. & Wu, W. P. Fibrinogen depleting agent batroxobin has a beneficial effect on experimental autoimmune encephalomyelitis. Cell. Mol. Neurobiol. 31, 437–448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Flick, M. J. et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo. J. Clin. Invest. 113, 1596–1606 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    Flick, M. J., Du, X. & Degen, J. L. Fibrin(ogen)–αMβ2 interactions regulate leukocyte function and innate immunity in vivo. Exp. Biol. Med. 229, 1105–1110 (2004).

    CAS  Article  Google Scholar 

  90. 90

    Huang, Y. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

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

    CAS  Article  Google Scholar 

  92. 92

    Schneider, J. A., Arvanitakis, Z., Bang, W. & Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197–2204 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  93. 93

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Bowman, G. L. et al. Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology 68, 1809–1814 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Ujiie, M., Dickstein, D. L., Carlow, D. A. & Jefferies, W. A. Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10, 463–470 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Scheltens, P. & Goos, J. D. Dementia in 2011: microbleeds in dementia—singing a different ARIA. Nat. Rev. Neurol. 8, 68–70 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Kirsch, W. et al. Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J. Alzheimers Dis. 17, 599–609 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Cullen, K. M., Kocsi, Z. & Stone, J. Microvascular pathology in the aging human brain: evidence that senile plaques are sites of microhaemorrhages. Neurobiol. Aging 27, 1786–1796 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    Merlini, M. & Akassoglou, K. Alzheimer disease makes new blood contacts. Blood 129, 2462–2463 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Hultman, K., Strickland, S. & Norris, E. H. The APOE ε4/ε4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients. J. Cereb. Blood Flow Metab. 33, 1251–1258 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    Ryu, J. K. & McLarnon J. G. A leaky blood-brain barrier, fibrinogen infiltration and microglial reactivity in inflamed Alzheimer's disease brain. J. Cell. Mol. Med. 13, 2911–2925 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Fiala, M. et al. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur. J. Clin. Invest. 32, 360–371 (2002).

    CAS  Article  Google Scholar 

  103. 103

    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 

  104. 104

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 105

    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  Google Scholar 

  106. 106

    Xu, G., Zhang, H., Zhang, S., Fan, X. & Liu, X. Plasma fibrinogen is associated with cognitive decline and risk for dementia in patients with mild cognitive impairment. Int. J. Clin. Pract. 62, 1070–1075 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    van Oijen, M., Witteman, J. C., Hofman, A., Koudstaal, P. J. & Breteler, M. M Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia. Stroke 36, 2637–2641 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Montagne, A., Zhao, Z. & Zlokovic, B. V. Alzheimer's disease: a matter of blood-brain barrier dysfunction? J. Exp. Med. 214, 3151–3169 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110

    McManus, R. M., Finucane, O. M., Wilk, M. M., Mills, K. H. G. & Lynch, M. A. FTY720 attenuates infection-induced enhancement of Aβ accumulation in APP/PS1 mice by modulating astrocytic activation. J. Neuroimmune Pharmacol. 12, 670–681 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Ahn, H. J. et al. A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer's disease mice. J. Exp. Med. 211, 1049–1062 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    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 

  114. 114

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    Soto, I. et al. APOE stabilization by exercise prevents aging neurovascular dysfunction and complement induction. PLOS Biol. 13, e1002279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    McLarnon, J. G. & Ryu, J. K. Relevance of Aβ1-42 intrahippocampal injection as an animal model of inflamed Alzheimer's disease brain. Curr. Alzheimer Res. 5, 475–480 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    Tripathy, D. et al. Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia. Front. Aging Neurosci. 5, 19 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Timmer, N. M. et al. Enoxaparin treatment administered at both early and late stages of amyloid β deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain Aβ levels. Neurobiol. Dis. 40, 340–347 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Bergamaschini, L. et al. Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and β-amyloid accumulation in a mouse model of Alzheimer's disease. J. Neurosci. 24, 4181–4186 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    Ahn, H. J. et al. Alzheimer's disease peptide β-amyloid interacts with fibrinogen and induces its oligomerization. Proc. Natl Acad. Sci. USA 107, 21812–21817 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  121. 121

    Zamolodchikov, D., Renne, T. & Strickland, S. The Alzheimer's disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII. J. Thromb. Haemost. 14, 995–1007 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Zamolodchikov, D. & Strickland, S. Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin. Blood 119, 3342–3351 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Oh, S. B. et al. Tissue plasminogen activator arrests Alzheimer's disease pathogenesis. Neurobiol. Aging 35, 511–519 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    Aso, E., Serrano, A. L., Munoz-Canoves, P. & Ferrer, I. Fibrinogen-derived γ377-395 peptide improves cognitive performance and reduces amyloid-β deposition, without altering inflammation, in AβPP/PS1 mice. J. Alzheimers Dis. 47, 403–412 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Chen, Z. L. et al. Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice. Blood 129, 2547–2556 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Sudre, C. H. et al. White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. Neuroimage Clin. 15, 171–180 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Thal, D. R. et al. Frontotemporal lobar degeneration FTLD-tau: preclinical lesions, vascular, and Alzheimer-related co-pathologies. J. Neural Transm. (Vienna) 122, 1007–1018 (2015).

    CAS  Article  Google Scholar 

  129. 129

    Winkler, E. A. et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 111–120 (2013).

    CAS  Article  Google Scholar 

  130. 130

    Evans, M. C., Couch, Y., Sibson, N. & Turner, M. R. Inflammation and neurovascular changes in amyotrophic lateral sclerosis. Mol. Cell Neurosci. 53, 34–41 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Kortekaas, R. et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Pisani, V. et al. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson's disease. J. Neuroinflamm. 9, 188 (2012).

    CAS  Article  Google Scholar 

  133. 133

    Gray, M. T. & Woulfe, J. M. Striatal blood–brain barrier permeability in Parkinson's disease. J. Cereb. Blood Flow Metab. 35, 747–750 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Shlosberg, D., Benifla, M., Kaufer, D. & Friedman, A. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat. Rev. Neurol. 6, 393–403 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Chodobski, A., Zink, B. J. & Szmydynger-Chodobska, J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. 2, 492–516 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Tomkins, O. et al. Blood–brain barrier disruption in post-traumatic epilepsy. J. Neurol. Neurosurg. Psychiatry 79, 774–777 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Korn, A., Golan, H., Melamed, I., Pascual-Marqui, R. & Friedman, A. Focal cortical dysfunction and blood-brain barrier disruption in patients with Postconcussion syndrome. J. Clin. Neurophysiol. 22, 1–9 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Hay, J. R., Johnson, V. E., Young, A. M., Smith, D. H. & Stewart, W. Blood–brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J. Neuropathol. Exp. Neurol. 74, 1147–1157 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

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

    CAS  Article  Google Scholar 

  140. 140

    Franklin, R. J. & Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Fancy, S. P., Chan, J. R., Baranzini, S. E., Franklin, R. J. & Rowitch, D. H. Myelin regeneration: a recapitulation of development? Annu. Rev. Neurosci. 34, 21–43 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Petersen, M. A. et al. Fibrinogen activates BMP signaling in oligodendrocyte progenitor cells and inhibits remyelination after vascular damage. Neuron 96, 1003–1012.e7 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Gallo, V. & Deneen, B. Glial development: the crossroads of regeneration and repair in the CNS. Neuron 83, 283–308 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Salazar, V. S., Gamer, L. W. & Rosen, V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12, 203–221 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  145. 145

    Wagner, D. O. et al. BMPs: from bone to body morphogenetic proteins. Sci. Signal 3, mr1 (2010).

    PubMed  PubMed Central  Google Scholar 

  146. 146

    Pera, M. F. & Tam, P. P. Extrinsic regulation of pluripotent stem cells. Nature 465, 713–720 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    See, J. et al. Oligodendrocyte maturation is inhibited by bone morphogenetic protein. Mol. Cell Neurosci. 26, 481–492 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    Gomes, W. A., Mehler, M. F. & Kessler, J. A. Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment. Dev. Biol. 255, 164–177 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    Lehnardt, S. et al. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci. 22, 2478–2486 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    Back, S. A., Gan, X., Li, Y., Rosenberg, P. A. & Volpe, J. J. Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion. J. Neurosci. 18, 6241–6253 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  151. 151

    Oka, A., Belliveau, M. J., Rosenberg, P. A. & Volpe, J. J. Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J. Neurosci. 13, 1441–1453 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Norris, E. H. & Strickland, S. Fibrinogen in the nervous system: glia beware. Neuron 96, 951–953 (2017).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Nave, K. A. & Ehrenreich, H. A bloody brake on myelin repair. Nature 553, 31–32 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Akassoglou, K., Kombrinck, K. W., Degen, J. L. & Strickland, S. Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J. Cell Biol. 149, 1157–1166 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Previtali, S. C. et al. The extracellular matrix affects axonal regeneration in peripheral neuropathies. Neurology 71, 322–331 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Zou, T. et al. Exogenous tissue plasminogen activator enhances peripheral nerve regeneration and functional recovery after injury in mice. J. Neuropathol. Exp. Neurol. 65, 78–86 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    Akassoglou, K., Akpinar, P., Murray, S. & Strickland, S. Fibrin is a regulator of Schwann cell migration after sciatic nerve injury in mice. Neurosci. Lett. 338, 185–188 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    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).

    CAS  Article  Google Scholar 

  159. 159

    Lam, C. K., Yoo, T., Hiner, B., Liu, Z. & Grutzendler, J. Embolus extravasation is an alternative mechanism for cerebral microvascular recanalization. Nature 465, 478–482 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Falati, S., Gross, P., Merrill-Skoloff, G., Furie, B. C. & Furie, B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat. Med. 8, 1175–1181 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  161. 161

    Tsai, Y. T. et al. Optical imaging of fibrin deposition to elucidate participation of mast cells in foreign body responses. Biomaterials 35, 2089–2096 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Kim, J. Y. et al. Direct imaging of cerebral thromboemboli using computed tomography and fibrin-targeted gold nanoparticles. Theranostics 5, 1098–1114 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Overoye-Chan, K. et al. EP-2104R: a fibrin-specific gadolinium-based MRI contrast agent for detection of thrombus. J. Am. Chem. Soc. 130, 6025–6039 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Blasi, F. et al. Multisite thrombus imaging and fibrin content estimation with a single whole-body PET scan in rats. Arterioscler Thromb. Vasc. Biol. 35, 2114–2121 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Olson, E. S. et al. In vivo fluorescence imaging of atherosclerotic plaques with activatable cell-penetrating peptides targeting thrombin activity. Integr. Biol. 4, 595–605 (2012).

    CAS  Article  Google Scholar 

  166. 166

    Chen, B. et al. Thrombin activity associated with neuronal damage during acute focal ischemia. J. Neurosci. 32, 7622–7631 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Whitney, M. et al. Ratiometric activatable cell-penetrating peptides provide rapid in vivo readout of thrombin activation. Angew. Chem. Int. Ed Engl. 52, 325–330 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Davalos, D. et al. Early detection of thrombin activity in neuroinflammatory disease. Ann. Neurol. 75, 303–308 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Lee, J. W. et al. Fibrinogen γ-A chain precursor in CSF: a candidate biomarker for Alzheimer's disease. BMC Neurol. 7, 14 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Craig-Schapiro, R. et al. Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis. PLOS ONE 6, e18850 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Vafadar-Isfahani, B. et al. Identification of SPARC-like 1 protein as part of a biomarker panel for Alzheimer's disease in cerebrospinal fluid. J. Alzheimers Dis. 28, 625–636 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Thambisetty, M. et al. Plasma biomarkers of brain atrophy in Alzheimer's disease. PLOS ONE 6, e28527 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Yang, H. Q. et al. Prognostic polypeptide blood plasma biomarkers of alzheimer's disease progression. J. Alzheimers Dis. 40, 659–666 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Ashton, N. J. et al. Blood protein predictors of brain amyloid for enrichment in clinical trials? Alzheimers Dement. 1, 48–60 (2015).

    Google Scholar 

  175. 175

    Conti, A. et al. Proteome study of human cerebrospinal fluid following traumatic brain injury indicates fibrin(ogen) degradation products as trauma-associated markers. J. Neurotrauma 21, 854–863 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  176. 176

    Zhang, Y. et al. Elevated fibrinogen levels in neuromyelitis optica is associated with severity of disease. Neurol. Sci. 37, 1823–1829 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  177. 177

    Gobel, K. et al. Prothrombin and factor X are elevated in multiple sclerosis patients. Ann. Neurol. 80, 946–951 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178

    Gobel, K. et al. Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells. Nat. Commun. 7, 11626 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179

    Zamolodchikov, D., Chen, Z. L., Conti, B. A., Renne, T. & Strickland, S. Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma. Proc. Natl Acad. Sci. USA 112, 4068–4073 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  180. 180

    Bergamaschini, L. et al. Activation of the contact system in cerebrospinal fluid of patients with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 12, 102–108 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  181. 181

    Hattori, K. et al. Increased cerebrospinal fluid fibrinogen in major depressive disorder. Sci. Rep. 5, 11412 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  182. 182

    Pollak, T. A. et al. The blood-brain barrier in psychosis. Lancet Psychiatry 5, 79–92 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  183. 183

    Patel, J. P. & Frey, B. N. Disruption in the blood–brain barrier: the missing link between brain and body inflammation in bipolar disorder? Neural Plast. 2015, 708306 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184

    Winkler, E. A. et al. Blood–spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc. Natl Acad. Sci. USA 111, E1035–E1042 (2014).

    CAS  Article  Google Scholar 

  185. 185

    Spencer, J. I., Bell, J. S. & DeLuca, G. C. Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood–brain barrier. J. Neurol. Neurosurg. Psychiatry 89, 42–52 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  186. 186

    Kraus, J. & Oschmann, P. The impact of interferon-β treatment on the blood–brain barrier. Drug Discov. Today 11, 755–762 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  187. 187

    Kunze, R. et al. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood–brain barrier integrity. Exp. Neurol. 266, 99–111 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  188. 188

    Nishihara, H. et al. Fingolimod prevents blood–brain barrier disruption induced by the sera from patients with multiple sclerosis. PLOS ONE 10, e0121488 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 189

    Luhder, F. et al. Laquinimod enhances central nervous system barrier functions. Neurobiol. Dis. 102, 60–69 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190

    Ifergan, I. et al. Statins reduce human blood–brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann. Neurol. 60, 45–55 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  191. 191

    Chataway, J. et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 383, 2213–2221 (2014).

    CAS  Article  Google Scholar 

  192. 192

    Zamolodchikov, D. & Strickland, S. The Alzheimer's disease peptide β-amyloid promotes thrombin generation through activation of coagulation factor XII: reply. J. Thromb. Haemost. 14, 1489 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  193. 193

    Zamolodchikov, D. & Strickland, S. A possible new role for Aβ in vascular and inflammatory dysfunction in Alzheimer's disease. Thromb. Res. 141, S59–S61 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  194. 194

    Claudio, L., Raine, C. S. & Brosnan, C. F. Evidence of persistent blood–brain barrier abnormalities in chronic- progressive multiple sclerosis. Acta Neuropathol. 90, 228–238 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  195. 195

    Inoue, A., Koh, C. S., Shimada, K., Yanagisawa, N. & Yoshimura, K. Suppression of cell-transferred experimental autoimmune encephalomyelitis in defibrinated Lewis rats. J. Neuroimmunol. 71, 131–137 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  196. 196

    Inoue, A. et al. Fibrin deposition in the central nervous system correlates with the degree of Theiler's murine encephalomyelitis virus-induced demyelinating disease. J. Neuroimmunol. 77, 185–194 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  197. 197

    Medved, L., Tsurupa, G. & Yakovlev, S. Conformational changes upon conversion of fibrinogen into fibrin. The mechanisms of exposure of cryptic sites. Ann. NY Acad. Sci. 936, 185–204 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  198. 198

    Engvall, E., Ruoslahti, E. & Miller, E. J. Affinity of fibronectin to collagens of different genetic types and to fibrinogen. J. Exp. Med. 147, 1584–1595 (1978).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  199. 199

    Suehiro, K. et al. Fibrinogen binds to integrin α5β1via the carboxyl-terminal RGD site of the Aα-chain. J. Biochem. 128, 705–710 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  200. 200

    Smith, J. W., Ruggeri, Z. M., Kunicki, T. J. & Cheresh, D. A. Interaction of integrins αvβ3 and glycoprotein IIb-IIIa with fibrinogen: differential peptide recognition accounts for distinct binding sites. J. Biol. Chem. 265, 12267–12271 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 201

    Chernousov, M. A. & Carey, D. J. αVβ8 integrin is a Schwann cell receptor for fibrin. Exp. Cell Res. 291, 514–524 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  202. 202

    Gorlatov, S. & Medved, L. Interaction of fibrin(ogen) with the endothelial cell receptor VE-cadherin: mapping of the receptor-binding site in the NH2-terminal portions of the fibrin β chains. Biochemistry 41, 4107–4116 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  203. 203

    Yakovlev, S. et al. Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes. Blood 119, 637–644 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  204. 204

    Altieri, D. C., Duperray, A., Plescia, J., Thornton, G. B. & Languino, L. R. Structural recognition of a novel fibrinogen γ chain sequence (117- 133) by intercellular adhesion molecule-1 mediates leukocyte- endothelium interaction. J. Biol. Chem. 270, 696–699 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  205. 205

    Fan, H. et al. Protective effects of Batroxobin on spinal cord injury in rats. Neurosci. Bull. 29, 501–508 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  206. 206

    Lu, W., Bhasin, M. & Tsirka, S. E. Involvement of tissue plasminogen activator in onset and effector phases of experimental allergic encephalomyelitis. J. Neurosci. 22, 10781–10789 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  207. 207

    Leech, S., Kirk, J., Plumb, J. & McQuaid, S. Persistent endothelial abnormalities and blood-brain barrier leak in primary and secondary progressive multiple sclerosis. Neuropathol. Appl. Neurobiol. 33, 86–98 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  208. 208

    Hochmeister, S. et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J. Neuropathol. Exp. Neurol. 65, 855–865 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  209. 209

    Montagne, A. et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat. Med. https://doi.org/10.1038/nm.4482 (2018). This study shows that fibrinogen depletion ameliorates neuropathology in pericyte-defficient mice.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  210. 210

    Gay, D. & Esiri, M. Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. Brain 114, 557–572 (1991).

    Article  Google Scholar 

  211. 211

    Lipinski, B. & Sajdel-Sulkowska, E. M. New insight into Alzheimer disease: demonstration of fibrin(ogen)-serum albumin insoluble deposits in brain tissue. Alzheimer Dis. Assoc. Disord. 20, 323–326 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  212. 212

    Brown, H. et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol. Appl. Neurobiol. 25, 331–340 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  213. 213

    Bardos, H., Molnar, P., Csecsei, G. & Adany, R. Fibrin deposition in primary and metastatic human brain tumours. Blood Coagul. Fibrinolysis 7, 536–548 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to L. Mucke and D. Reich for critical reading of the manuscript, T. Roberts and J. Carroll for graphics and G. Howard for editorial assistance. The authors are supported by the US National Institutes of Health (NIH), National Institute of Child Health and Human Development (NICHD) K12-HD072222 grant and a Pediatric Scientist Development Program fellowship (supported by March of Dimes 4-FY10-461 and NIH/NICHD K12-HD000850) to M.A.P, a Race to Erase MS Young Investigator Award and American Heart Association Scientist Development grant to J.K.R and the National Multiple Sclerosis Society grant RG4985, NIH/NINDS grant R35 NS097976, the Conrad N. Hilton Foundation grant and US Department of Defense MS160082 grant to K.A.

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K.A., M.A.P. and J.K.R. researched data for the article, made substantial contributions to the discussion of content and contributed to the writing, review and editing of the manuscript before submission.

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Correspondence to Katerina Akassoglou.

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K.A. is a co-founder of MedaRed. K.A. and J.K.R. are named inventors in patents and patent applications. Their interests are managed by the Gladstone Institutes in accordance with its conflict of interest policy.

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Petersen, M., Ryu, J. & Akassoglou, K. Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat Rev Neurosci 19, 283–301 (2018). https://doi.org/10.1038/nrn.2018.13

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