Skip to main content
SpringerLink
Log in

The Role of Galectin-3: From Oligodendroglial Differentiation and Myelination to Demyelination and Remyelination Processes in a Cuprizone-Induced Demyelination Model

  • Chapter
  • First Online:
Glial Cells in Health and Disease of the CNS

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 949))

Abstract

The aim of this work was to combine our previously published results with our new data to show how galectin-3 (Gal-3) controls myelin integrity and function, promotes oligodendroglial cell differentiation, and regulates microglial responses to limit cuprizone- (CPZ)-induced demyelination and foster remyelination. In this study, 8-week-old Gal-3-deficient (Lgals3 −/−) and wild type (WT) mice were fed a diet containing 0.2 % CPZ w/w for 6 weeks, after which CPZ was withdrawn in order to allow remyelination. Our results show that remyelination was less efficient in Lgals3 −/− than in WT mice. Electron microscopic images from remyelinated sections in Lgals3 −/− mice revealed collapsed axons with a defective myelin wrap, while remyelinated WT mice had normal axons without relevant myelin wrap disruption. MMP-3 expression increased during remyelination in WT but not in Lgals3 −/− mice. The number of CD45+, TNFα+ and TREM-2b+ cells decreased only in WT mice only, with no alterations in Lgals3 −/− mice during demyelination and remyelination. Therefore, Gal-3 influences remyelination by mechanisms involving the tuning of microglial cells, modulation of MMP activity, and changes in myelin architecture.

L.A. Pasquini and J.M. Pasquini contributed equally to this work and should be considered as co-senior.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

MMPs:

Matrix metalloproteinases

Gal-3:

Galectin-3

Lgals3 −/− :

Gal-3-deficient

WT:

Wild type

CPZ:

Cuprizone

CRD:

Carbohydrate-recognition domain

CNS:

Central nervous system

OLG:

Oligodendrocyte

EAE:

Experimental Autoimmune Encephalomyelitis

CC:

Corpus callosum

OPC:

Oligodendrocyte precursor cells

MBP:

Myelin basic protein

PBS:

Phosphate buffered saline

PFA:

Paraformaldehyde

SVZ:

Subventricular zone

EM:

Electron Microscopy

GFAP:

Glial Fibrillary Acidic Protein

IOD:

Integrated optical density

References

  • Chandler S, Coates R, Gearing A, Lury J, Wells G, Bone E (1995) Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett 201:223–226

    Article  CAS  PubMed  Google Scholar 

  • Chandler S, Cossins J, Lury J, Wells G (1996) Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun 228:421–429

    Article  CAS  PubMed  Google Scholar 

  • Chernoff GF (1981) Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J Hered 72:128

    CAS  PubMed  Google Scholar 

  • David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:388–399

    Article  CAS  PubMed  Google Scholar 

  • Franco-Pons N, Torrente M, Colomina MT, Vilella E (2007) Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett 169:205–213

    Article  CAS  PubMed  Google Scholar 

  • Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 11:839–855

    Article  Google Scholar 

  • Franklin RJ, Kotter MR (2008) The biology of CNS remyelination: the key to therapeutic advances. J Neurol 255:19–25

    Article  CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10:1387–1394

    Article  CAS  PubMed  Google Scholar 

  • Hansmann F, Herder V, Kalkuhl A, Haist V, Zhang N, Schaudien D, Deschl U, Baumgärtner W, Ulrich R (2012) Matrix metalloproteinase-12 deficiency ameliorates clinical course and demyelination in Theiler’s murine encephalomyelitis. Acta Neuropathol 124:127–142

    Article  CAS  PubMed  Google Scholar 

  • Hoyos HC, Rinaldi M, Mendez-Huergo SP, Marder M, Rabinovich GA, Pasquini JM, Pasquini LA (2014) Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination. Neurobiol Dis 62:441–455

    Article  CAS  PubMed  Google Scholar 

  • Hsu DK, Yang RY, Pan Z, Yu L, Salomon DR, Fung-Leung WP, Liu FT (2000) Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses. Am J Pathol 156:1073–1083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang HR, Al Rasebi Z, Mensah-Brown E, Shahin A, Xu D, Goodyear CS, Fukada SY, Liu FT, Liew FY, Lukic ML (2009) Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J. Immunol 182:1167–1173

    Article  CAS  PubMed  Google Scholar 

  • Kim YS, Joh TH (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson’s disease. Exp Mol Med 38:333–347

    Article  CAS  PubMed  Google Scholar 

  • Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118:723–736

    Article  PubMed  Google Scholar 

  • Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332

    Article  CAS  PubMed  Google Scholar 

  • Lalancette-Hébert M, Swarup V, Beaulieu JM, Bohacek I, Abdelhamid E, Weng YC, Sato S, Kriz J (2012) Galectin-3 is required for resident microglia activation and proliferation in response to ischemic injury. J Neurosci 32:10383–10395

    Article  PubMed  Google Scholar 

  • Li Y, Komai-Koma M, Gilchrist DS, Hsu DK, Liu FT, Springall T, Xu D (2008) Galectin-3 is a negative regulator of lipopolysaccharide-mediated inflammation. J Immunol 181:2781–2789

    Article  CAS  PubMed  Google Scholar 

  • Mason JL, Langaman C, Morell P, Suzuki K, Matsushima GK (2001) Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol Appl Neurobiol 27:50–58

    Article  CAS  PubMed  Google Scholar 

  • Masuda-Nakagawa LM, Muller KJ, Nicholls JG (1993) Axonal sprouting and laminin appearance after destruction of glial sheaths. Proc Natl Acad Sci USA 90(11):4966–4970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsushima GK, Morell P (2001) The neurotoxicant cuprizone as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116

    Article  CAS  PubMed  Google Scholar 

  • McMahon EJ, Suzuki K, Matsushima GK (2002) Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood–brain barrier. J Neuroimmunol 130:32–45

    Article  CAS  PubMed  Google Scholar 

  • Mok SW, Thelen KM, Riemer C, Bamme T, Gültner S, Lütjohann D, Baier M (2006) Simvastatin prolongs survival times in prion infections of the central nervous system. Biochem Biophys Res Commun 348:697–702

    Article  CAS  PubMed  Google Scholar 

  • Mok SW, Riemer C, Madela K, Hsu DK, Liu FT, Gültner S, Heise I, Baier M (2007) Role of galectin-3 in prion infections of the CNS. Biochem Biophys Res Commun 359:672–678

    Article  CAS  PubMed  Google Scholar 

  • Ochieng J, Fridman R, Nangia-Makker P, Kleiner DE, Liotta LA, Stetler-Stevenson WG, Raz A (1994) Galectin-3 is a novel substrate for human matrix metalloproteinases-2 and -9. Biochemistry 33:14109–14114

    Article  CAS  PubMed  Google Scholar 

  • Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, Boddeke HW (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60:306–321

    Article  PubMed  Google Scholar 

  • Pasquini LA, Millet V, Hoyos HC, Giannoni JP, Croci DO, Marder M, Liu FT, Rabinovich GA, Pasquini JM (2011) Galectin-3 drives oligodendrocyte differentiation to control myelin integrity and function. Cell Death Differ 18:1746–1756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rabinovich GA, Croci DO (2012) Regulatory circuits mediated by lectin–glycan interactions in autoimmunity and cancer. Immunity 36:322–335

    Article  CAS  PubMed  Google Scholar 

  • Rabinovich GA, Toscano MA (2009) Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9:338–352

    Article  CAS  PubMed  Google Scholar 

  • Rabinovich GA, Toscano MA, Jackson SS, Vasta GR (2007) Functions of cell surface galectin glycoprotein lattices. Curr Opin Struct Biol 17:513–520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ransohoff RM, Brown MA (2012) Innate immunity in the Central Nervous System. J Clin Invest 122:1164–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170:1713–1724

    Article  PubMed  PubMed Central  Google Scholar 

  • Riemer C, Neidhold S, Burwinkel M, Schwarz A, Schultz J, Krätzschmar J, Mönning U, Baier M (2004) Gene expression profiling of scrapie-infected brain tissue. Biochem Biophys Res Commun 323:556–564

    Article  CAS  PubMed  Google Scholar 

  • Shiryaev SA, Savinov AY, Cieplak P, Ratnikov BI, Motamedchaboki K, Smith JW, Strongin AY (2009) Matrix metalloproteinase proteolysis of the myelin basic protein isoforms is a source of immunogenic peptides in autoimmune multiple sclerosis. PLoS One 4(3):e4952

    Article  PubMed  PubMed Central  Google Scholar 

  • Skuljec J, Gudi V, Ulrich R, Frichert K, Yildiz O, Pul R, Voss EV, Wissel K, Baumgärtner W, Stangel M (2011) Matrix metalloproteinases and their tissue inhibitors in cuprizone-induced demyelination and remyelination of brain white and gray matter. J Neuropathol Exp Neurol 70:758–769

    Article  CAS  PubMed  Google Scholar 

  • Smith GS, Sambroska B, Hawley SP, Klaiman JM, Gillis TE, Jones N, Boggs JM, Harauz G (2013) Nucleus-localized 21.5-kDa myelin basic protein promotes oligodendrocyte proliferation and enhances neurite outgrowth in coculture, unlike the plasma membrane-associated 18.5-kDa isoform. J Neurosci Res 91:349–362

    Article  CAS  PubMed  Google Scholar 

  • Stadelmann C (2011) Multiple sclerosis as a neurodegenerative disease: pathology, mechanisms and therapeutic implications. Curr Opin Neurol 24:224–229

    Article  CAS  PubMed  Google Scholar 

  • Stancic M, Slijepcevic D, Nomden A, Vos MJ, de Jonge JC, Sikkema AH, Gabius HJ, Hoekstra D, Baron W (2012) Galectin-4, a novel neuronal regulator of myelination. Glia 60:919–935

    Article  PubMed  Google Scholar 

  • Ulrich R, Gerhauser I, Seeliger F, Baumgärtner W, Alldinger S (2005) Matrix metalloproteinases and their inhibitors in the developing mouse brain and spinal cord: A reverse transcription quantitative polymerase chain reaction study. Dev Neurosci 27:408–418

    Article  CAS  PubMed  Google Scholar 

  • Ulrich R, Baumgärtner W, Gerhauser I, Seeliger F, Haist V, Deschl U, Alldinger S (2006) MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating Theiler murine encephalomyelitis. J Neuropathol Exp Neurol 65:783–793

    Article  CAS  PubMed  Google Scholar 

  • Ulrich R, Seeliger F, Kreutzer M, Germann PG, Baumgärtner W (2008) Limited remyelination in Theiler’s murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells. Neuropathol Appl Neurobiol 34:603–620

    Article  CAS  PubMed  Google Scholar 

  • von Bernhardi R, Muller KJ (1995) Repair of the central nervous system: lessons from lesions in leeches. J Neurobiol 27(3):353–366

    Article  Google Scholar 

  • Voss EV, Škuljec J, Gudi V, Skripuletz T, Pul R, Trebst C, Stangel M (2012) Characterisation of microglia during de- and remyelination: can they create a repair promoting environment? Neurobiol Dis 45:519–528

    Google Scholar 

  • Williams A, Piaton G, Lubetzki C (2007) Astrocytes-friends or foes in multiple sclerosis? Glia 55:1300–1312

    Google Scholar 

  • Xu H, Yang HJ, Zhang Y, Clough R, Browning R, Li XM (2009) Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci 123:418–429

    Article  CAS  PubMed  Google Scholar 

  • Yang RY, Rabinovich GA, Liu FT (2008) Galectins: structure, function and therapeutic potential. Expert Rev Mol Med 10:e17

    Article  PubMed  Google Scholar 

  • Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 7:502–511

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, School of Pharmacy and Biochemistry, Institute of Chemistry and Biological Physical Chemistry (IQUIFIB), Buenos Aires, Argentina

    H. C. Hoyos, Mariel Marder, L. A. Pasquini & J. M. Pasquini

  2. School of Pharmacy and Biochemistry, University of Buenos Aires and National Research Council (CONICET), Buenos Aires, Argentina

    H. C. Hoyos, Mariel Marder, L. A. Pasquini & J. M. Pasquini

  3. Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany

    R. Ulrich

  4. Department of Neurology, Hannover Medical School, Hannover, Germany

    V. Gudi & M. Stangel

  5. Center for System Neurosciences, Hannover, Germany

    V. Gudi & M. Stangel

  6. Laboratory of Immunopathology, Institute of Biology and Experimental Medicine (IBYME; CONICET), C1428, Buenos Aires, Argentina

    G. A. Rabinovich

  7. Laboratory of Functional Glycomics, Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires, C1428, Buenos Aires, Argentina

    G. A. Rabinovich

  8. Dpto. de Qca Biol, FFyB-UBA, Junín 956, C1113, Bs as, Argentina

    L. A. Pasquini & J. M. Pasquini

Authors
  1. H. C. Hoyos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariel Marder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Ulrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. Gudi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Stangel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. A. Rabinovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L. A. Pasquini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. M. Pasquini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. M. Pasquini .

Editor information

Editors and Affiliations

  1. Faculty of Medicine Professor of Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile

    Rommy von Bernhardi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hoyos, H.C. et al. (2016). The Role of Galectin-3: From Oligodendroglial Differentiation and Myelination to Demyelination and Remyelination Processes in a Cuprizone-Induced Demyelination Model. In: von Bernhardi, R. (eds) Glial Cells in Health and Disease of the CNS. Advances in Experimental Medicine and Biology, vol 949. Springer, Cham. https://doi.org/10.1007/978-3-319-40764-7_15

Download citation

Publish with us

Policies and ethics

Search

Navigation