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.
This is a preview of subscription content
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707–720 (2013).
Vemuri, P. et al. Vascular and amyloid pathologies are independent predictors of cognitive decline in normal elderly. Brain 138, 761–771 (2015).
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).
Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).
Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
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).
Davalos, D. & Akassoglou, K. Fibrinogen as a key regulator of inflammation in disease. Semin. Immunopathol. 34, 43–62 (2012).
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.
Davalos, D. et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat. Commun. 3, 1227 (2012).
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).
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.
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).
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.
Liebner, S., Czupalla, C. J. & Wolburg, H. Current concepts of blood-brain barrier development. Int. J. Dev. Biol. 55, 467–476 (2011).
Iadecola, C. The Neurovascular Unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017).
Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat. Rev. Neurosci. 12, 723–738 (2011).
Tietz, S. & Engelhardt, B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J. Cell Biol. 209, 493–506 (2015).
Knowland, D. et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood–brain barrier breakdown in stroke. Neuron 82, 603–617 (2014).
Baeten, K. M. & Akassoglou, K. Extracellular matrix and matrix receptors in blood–brain barrier formation and stroke. Dev. Neurobiol. 71, 1018–1039 (2011).
Zhao, Z., Nelson, A. R., Betsholtz, C. & Zlokovic, B. V. Establishment and dysfunction of the blood–brain barrier. Cell 163, 1064–1078 (2015).
Thomas, W. S. et al. Tissue factor contributes to microvascular defects after focal cerebral ischemia. Stroke 24, 847–853 (1993).
Akassoglou, K. & Strickland, S. Nervous system pathology: the fibrin perspective. Biol. Chem. 383, 37–45 (2002).
Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).
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).
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).
Tennent, G. A. et al. Human plasma fibrinogen is synthesized in the liver. Blood 109, 1971–1974 (2007).
Weisel, J. W. Fibrinogen and fibrin. Adv. Protein Chem. 70, 247–299 (2005).
Lord, S. T. Molecular mechanisms affecting fibrin structure and stability. Arterioscler Thromb. Vasc. Biol. 31, 494–499 (2011).
Mosesson, M. W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 3, 1894–1904 (2005).
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).
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).
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).
Castellino, F. J. & Ploplis, V. A. Structure and function of the plasminogen/plasmin system. Thromb. Haemost. 93, 647–654 (2005).
Bardehle, S., Rafalski, V. A. & Akassoglou, K. Breaking boundaries-coagulation and fibrinolysis at the neuro-vascular interface. Front. Cell Neurosci. 9, 354 (2015).
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).
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).
Laurens, N., Koolwijk, P. & de Maat, M. P. Fibrin structure and wound healing. J. Thromb. Haemost. 4, 932–939 (2006).
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).
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.
Romer, J. et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat. Med. 2, 287–292 (1996).
Motley, M. P. et al. A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood 127, 1085–1096 (2016).
Doolittle, R. F. A detailed consideration of a principal domain of vertebrate fibrinogen and its relatives. Protein Sci. 1, 1563–1577 (1992).
Doolittle, R. F., McNamara, K. & Lin, K. Correlating structure and function during the evolution of fibrinogen-related domains. Protein Sci. 21, 1808–1823 (2012).
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).
Marazzi, S. et al. Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes. J. Immunol. 161, 138–147 (1998).
Chiquet-Ehrismann, R. & Tucker, R. P. Tenascins and the importance of adhesion modulation. Cold Spring Harb. Perspect. Biol. 3, a004960 (2011).
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).
Powell, P. A., Wesley, C., Spencer, S. & Cagan, R. L. Scabrous complexes with Notch to mediate boundary formation. Nature 409, 626–630 (2001).
Lassmann, H. Multiple sclerosis pathology: evolution of pathogenetic concepts. Brain Pathol. 15, 217–222 (2005).
Lassmann, H., Bruck, W. & Lucchinetti, C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol. Med. 7, 115–121 (2001).
Lucchinetti, C. F., Brueck, W., Rodriguez, M. & Lassmann, H. Multiple sclerosis: lessons from neuropathology. Semin. Neurol. 18, 337–349 (1998).
Rindficisch, E. Histologisches detail zu der grauen degeneration von gehirn und ruckenmark. Arch. Pathol. Anat. Physiol. 26, 474–483 (1863).
Reich, D. S., Lucchinetti, C. F. & Calabresi, P. A. Multiple sclerosis. N. Engl. J. Med. 378, 169–180 (2018).
Grossman, R. I. et al. Multiple sclerosis: serial study of gadolinium-enhanced MR imaging. Radiology 169, 117–122 (1988).
Miller, D. H. et al. Serial gadolinium enhanced magnetic resonance imaging in multiple sclerosis. Brain 111, 927–939 (1988).
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).
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).
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).
Gaitan, M. I. et al. Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions. Ann. Neurol. 70, 22–29 (2011).
Bruck, W. et al. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann. Neurol. 42, 783–793 (1997).
Katz, D. et al. Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann. Neurol. 34, 661–669 (1993).
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).
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).
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).
Han, M. H. et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076–1081 (2008).
Yates, R. L. et al. Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann. Neurol. 82, 259–270 (2017).
Gveric, D. et al. Plasminogen activators in multiple sclerosis lesions: implications for the inflammatory response and axonal damage. Brain 124, 1978–1988 (2001).
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).
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.
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).
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).
Adams, R. D. & Kubik, C. S. The morbid anatomy of the demyelinative disease. Am. J. Med. 12, 510–546 (1952).
Barnett, M. H. & Prineas, J. W. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann. Neurol. 55, 458–468 (2004).
Maggi, P. et al. The formation of inflammatory demyelinated lesions in cerebral white matter. Ann. Neurol. 76, 594–608 (2014).
Ryu, J. K. et al. Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat. Commun. 6, 8164 (2015).
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.
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).
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).
Millien, V. O. et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341, 792–796 (2013).
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).
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).
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).
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).
Hanspers, K., Akassoglou, K. & Mendiola, A. S. Fibrin complement receptor 3 signaling pathway (Homo sapiens). Wikipathways.org/Index.php/Pathway:WP4136 (2017).
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.
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).
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).
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).
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).
Huang, Y. & Mucke, L. Alzheimer mechanisms and therapeutic strategies. Cell 148, 1204–1222 (2012).
Iadecola, C. The pathobiology of vascular dementia. Neuron 80, 844–866 (2013).
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).
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).
Bowman, G. L. et al. Blood-brain barrier impairment in Alzheimer disease: stability and functional significance. Neurology 68, 1809–1814 (2007).
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).
Scheltens, P. & Goos, J. D. Dementia in 2011: microbleeds in dementia—singing a different ARIA. Nat. Rev. Neurol. 8, 68–70 (2012).
Kirsch, W. et al. Serial susceptibility weighted MRI measures brain iron and microbleeds in dementia. J. Alzheimers Dis. 17, 599–609 (2009).
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).
Merlini, M. & Akassoglou, K. Alzheimer disease makes new blood contacts. Blood 129, 2462–2463 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
Montagne, A., Zhao, Z. & Zlokovic, B. V. Alzheimer's disease: a matter of blood-brain barrier dysfunction? J. Exp. Med. 214, 3151–3169 (2017).
Winkler, E. A. et al. GLUT1 reductions exacerbate Alzheimer's disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521–530 (2015).
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).
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).
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).
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).
Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).
Soto, I. et al. APOE stabilization by exercise prevents aging neurovascular dysfunction and complement induction. PLOS Biol. 13, e1002279 (2015).
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).
Tripathy, D. et al. Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia. Front. Aging Neurosci. 5, 19 (2013).
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).
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).
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).
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).
Zamolodchikov, D. & Strickland, S. Aβ delays fibrin clot lysis by altering fibrin structure and attenuating plasminogen binding to fibrin. Blood 119, 3342–3351 (2012).
Oh, S. B. et al. Tissue plasminogen activator arrests Alzheimer's disease pathogenesis. Neurobiol. Aging 35, 511–519 (2014).
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).
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).
Bien-Ly, N. et al. Lack of widespread BBB disruption in Alzheimer's disease models: focus on therapeutic antibodies. Neuron 88, 289–297 (2015).
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).
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).
Winkler, E. A. et al. Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol. 125, 111–120 (2013).
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).
Kortekaas, R. et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann. Neurol. 57, 176–179 (2005).
Pisani, V. et al. Increased blood-cerebrospinal fluid transfer of albumin in advanced Parkinson's disease. J. Neuroinflamm. 9, 188 (2012).
Gray, M. T. & Woulfe, J. M. Striatal blood–brain barrier permeability in Parkinson's disease. J. Cereb. Blood Flow Metab. 35, 747–750 (2015).
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).
Chodobski, A., Zink, B. J. & Szmydynger-Chodobska, J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res. 2, 492–516 (2011).
Tomkins, O. et al. Blood–brain barrier disruption in post-traumatic epilepsy. J. Neurol. Neurosurg. Psychiatry 79, 774–777 (2008).
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).
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).
Armulik, A. et al. Pericytes regulate the blood–brain barrier. Nature 468, 557–561 (2010).
Franklin, R. J. & Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).
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).
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).
Gallo, V. & Deneen, B. Glial development: the crossroads of regeneration and repair in the CNS. Neuron 83, 283–308 (2014).
Salazar, V. S., Gamer, L. W. & Rosen, V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12, 203–221 (2016).
Wagner, D. O. et al. BMPs: from bone to body morphogenetic proteins. Sci. Signal 3, mr1 (2010).
Pera, M. F. & Tam, P. P. Extrinsic regulation of pluripotent stem cells. Nature 465, 713–720 (2010).
See, J. et al. Oligodendrocyte maturation is inhibited by bone morphogenetic protein. Mol. Cell Neurosci. 26, 481–492 (2004).
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).
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).
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).
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).
Norris, E. H. & Strickland, S. Fibrinogen in the nervous system: glia beware. Neuron 96, 951–953 (2017).
Nave, K. A. & Ehrenreich, H. A bloody brake on myelin repair. Nature 553, 31–32 (2018).
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).
Previtali, S. C. et al. The extracellular matrix affects axonal regeneration in peripheral neuropathies. Neurology 71, 322–331 (2008).
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).
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).
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).
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).
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).
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).
Kim, J. Y. et al. Direct imaging of cerebral thromboemboli using computed tomography and fibrin-targeted gold nanoparticles. Theranostics 5, 1098–1114 (2015).
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).
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).
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).
Chen, B. et al. Thrombin activity associated with neuronal damage during acute focal ischemia. J. Neurosci. 32, 7622–7631 (2012).
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).
Davalos, D. et al. Early detection of thrombin activity in neuroinflammatory disease. Ann. Neurol. 75, 303–308 (2014).
Lee, J. W. et al. Fibrinogen γ-A chain precursor in CSF: a candidate biomarker for Alzheimer's disease. BMC Neurol. 7, 14 (2007).
Craig-Schapiro, R. et al. Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis. PLOS ONE 6, e18850 (2011).
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).
Thambisetty, M. et al. Plasma biomarkers of brain atrophy in Alzheimer's disease. PLOS ONE 6, e28527 (2011).
Yang, H. Q. et al. Prognostic polypeptide blood plasma biomarkers of alzheimer's disease progression. J. Alzheimers Dis. 40, 659–666 (2014).
Ashton, N. J. et al. Blood protein predictors of brain amyloid for enrichment in clinical trials? Alzheimers Dement. 1, 48–60 (2015).
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).
Zhang, Y. et al. Elevated fibrinogen levels in neuromyelitis optica is associated with severity of disease. Neurol. Sci. 37, 1823–1829 (2016).
Gobel, K. et al. Prothrombin and factor X are elevated in multiple sclerosis patients. Ann. Neurol. 80, 946–951 (2016).
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).
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).
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).
Hattori, K. et al. Increased cerebrospinal fluid fibrinogen in major depressive disorder. Sci. Rep. 5, 11412 (2015).
Pollak, T. A. et al. The blood-brain barrier in psychosis. Lancet Psychiatry 5, 79–92 (2018).
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).
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).
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).
Kraus, J. & Oschmann, P. The impact of interferon-β treatment on the blood–brain barrier. Drug Discov. Today 11, 755–762 (2006).
Kunze, R. et al. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood–brain barrier integrity. Exp. Neurol. 266, 99–111 (2015).
Nishihara, H. et al. Fingolimod prevents blood–brain barrier disruption induced by the sera from patients with multiple sclerosis. PLOS ONE 10, e0121488 (2015).
Luhder, F. et al. Laquinimod enhances central nervous system barrier functions. Neurobiol. Dis. 102, 60–69 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Suehiro, K. et al. Fibrinogen binds to integrin α5β1via the carboxyl-terminal RGD site of the Aα-chain. J. Biochem. 128, 705–710 (2000).
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).
Chernousov, M. A. & Carey, D. J. αVβ8 integrin is a Schwann cell receptor for fibrin. Exp. Cell Res. 291, 514–524 (2003).
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).
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).
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).
Fan, H. et al. Protective effects of Batroxobin on spinal cord injury in rats. Neurosci. Bull. 29, 501–508 (2013).
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).
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).
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).
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.
Gay, D. & Esiri, M. Blood-brain barrier damage in acute multiple sclerosis plaques. An immunocytological study. Brain 114, 557–572 (1991).
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).
Brown, H. et al. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol. Appl. Neurobiol. 25, 331–340 (1999).
Bardos, H., Molnar, P., Csecsei, G. & Adany, R. Fibrin deposition in primary and metastatic human brain tumours. Blood Coagul. Fibrinolysis 7, 536–548 (1996).
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.
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.
About this article
Cite this article
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
Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics
Journal of Neuroinflammation (2022)
Nature Reviews Neurology (2022)
Nature Reviews Neurology (2022)
Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis
Molecular Psychiatry (2022)
Nature Reviews Drug Discovery (2022)