Skip to main content

Age-Related and Cuprizone-Induced Changes in Myelin and Transcription Factor Gene Expression and in Oligodendrocyte Cell Densities in the Rostral Corpus Callosum of Mice

Cellular and Molecular Neurobiology volume 30, pages 607–629 (2010)Cite this article

Abstract

During aging, there is a decrease both in the stability of central nervous system (CNS) myelin once formed and in the efficiency of its repair by oligodendrocytes (OLs). To study CNS remyelination during aging, we used the cuprizone (a copper chelator) mouse model. Inclusion of cuprizone in the diet kills mature OLs and demyelinates axons in the rostral corpus callosum (CC) of mice, which enabled us to characterize age-related changes (i.e., 2–16 months of age) in glial cell response during the recruitment (i.e., demyelination) and differentiation (i.e., remyelination) phases of myelin repair. We have found that the time between 12 and 16 months of age is a critical period during which there is an age-related decrease in the number of OL lineage cells (Olig2Nuc+ve/GFAP−ve cells) in the rostral CC of both control mice and mice recovering from cuprizone-induced demyelination. Our results also show there was an age-related impaired recruitment of progenitor cells to replace lost OLs in spite of there being no major age-related decrease in the size of the progenitor cell pool (PDGFαR+ve/GFAP−ve, and Olig2Nuc +ve/PDGFαR+ve cells). However, there were cuprizone-induced increased numbers of astrocyte progenitor cells (Olig2Cyto+ve/PDGFαR+ve) in these same mice; thus PDGFαR+ve progenitor cells in mice as old as 16 months of age retain the ability to differentiate into astrocytes, with this fate choice occurring following cytoplasmic translocation of Olig2. These data reveal for the first time age-related differences in the differentiation of PDGFαR+ve progenitor cells into OLs and astrocytes and lead us to suggest that during aging there must be a transcriptional switch mechanism in the progenitor cell fate choice in favor of astrocytes. This may at least partially explain the age-related decrease in efficiency of OL myelination and remyelination.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

References

  • Ando S, Tanaka Y, Toyoda Y, Kon K (2003) Turnover of myelin lipids in aging brain. Neurochem Res 28:5–13

    Article  CAS  PubMed  Google Scholar 

  • Armstrong RC, Le TQ, Frost EE, Borke RC, Vana AC (2002) Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter. J Neurosci 22:8574–8585

    CAS  PubMed  Google Scholar 

  • Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD (2004) bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science 306:2111–2115

    Article  CAS  PubMed  Google Scholar 

  • Bakker DA, Ludwin SK (1987) Blood-brain barrier permeability during Cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases. J Neurol Sci 78:125–137

    Article  CAS  PubMed  Google Scholar 

  • Bartzokis G (2004a) Age-related myelin breakdown: a developmental model of cognitive decline and Alzheimer’s disease. Neurobiol Aging 25:5–18 author reply 49–62

    Article  CAS  PubMed  Google Scholar 

  • Bartzokis G (2004b) Author’s response to commentaries. Quadratic trajectories of brain myelin content: unifying construct for neuropsychiatric disorders. Neurobiol Aging 25:49–62

    Article  CAS  Google Scholar 

  • Bartzokis G, Sultzer D, Lu PH, Nuechterlein KH, Mintz J, Cummings JL (2004a) Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical “disconnection” in aging and Alzheimer’s disease. Neurobiol Aging 25:843–851

    Article  CAS  PubMed  Google Scholar 

  • Bartzokis G, Tishler TA, Shin IS, Lu PH, Cummings JL (2004b) Brain ferritin iron as a risk factor for age at onset in neurodegenerative diseases. Ann N Y Acad Sci 1012:224–236

    Article  CAS  PubMed  Google Scholar 

  • Benes FM (2004) A disturbance of late myelination as a trigger for Alzheimer’s disease. Neurobiol Aging 25:41–43

    Article  CAS  PubMed  Google Scholar 

  • Blakemore WF, Crang AJ (1988) Extensive oligodendrocyte remyelination following injection of cultured central nervous system cells into demyelinating lesions in adult central nervous system. Dev Neurosci 10:1–11

    Article  CAS  PubMed  Google Scholar 

  • Blakemore WF, Crang AJ, Franklin RJM (1990) Transplantation of glial cell cultures into areas of demyelination in the adult CNS. Prog Brain Res 82:225–232

    Article  CAS  PubMed  Google Scholar 

  • Boyd JG, Lee J, Skihar V, Doucette R, Kawaja MD (2004) LacZ-expressing olfactory ensheathing cells do not associate with myelinated axons after implantation into the compressed spinal cord. Proc Natl Acad Sci U S A 101:2162–2166

    Article  CAS  PubMed  Google Scholar 

  • Braak H, Del Tredici K (2004) Poor and protracted myelination as a contributory factor to neurodegenerative disorders. Neurobiol Aging 25:19–23

    Article  CAS  PubMed  Google Scholar 

  • Carey EM, Freeman NM (1983) Biochemical changes in Cuprizone-induced spongiform encephalopathy. I. Changes in the activities of 2′,3′-cyclic nucleotide 3′-phosphohydrolase, oligodendroglial ceramide galactosyl transferase, and the hydrolysis of the alkenyl group of alkenyl, acyl-glycerophospholipids by plasmalogenase in different regions of the brain. Neurochem Res 8:1029–1044

    Article  CAS  PubMed  Google Scholar 

  • Cassiani-Ingoni R, Coksaygan T, Xue H, Reichert-Scrivner SA, Wiendl H, Rao MS, Magnus T (2006) Cytoplasmic translocation of Olig2 in adult glial progenitors marks the generation of reactive astrocytes following autoimmune inflammation. Exp Neurol 201:349–358

    Article  CAS  PubMed  Google Scholar 

  • Chari DM, Crang AJ, Blakemore WF (2003) Decline in rate of colonization of oligodendrocyte progenitor cell (OPC)-depleted tissue by adult OPCs with age. J Neuropathol Exp Neurol 62:908–916

    CAS  PubMed  Google Scholar 

  • Collarini EJ, Pringle N, Mudhar H, Stevens G, Kuhn R, Monuki ES, Lemke G, Richardson WD (1991) Growth factors and transcription factors in oligodendrocyte development. J Cell Sci Suppl 15:117–123

    CAS  PubMed  Google Scholar 

  • Connor JR (2004) Myelin breakdown in Alzheimer’s disease: a commentary. Neurobiol Aging 25:45–47

    Article  CAS  PubMed  Google Scholar 

  • Franklin RJ, Zhao C, Sim FJ (2002) Ageing and CNS remyelination. Neuroreport 13:923–928

    Article  PubMed  Google Scholar 

  • Fukuda S, Kondo T, Takebayashi H, Taga T (2004) Negative regulatory effect of an oligodendrocyte bHLH factor OLIG2 on the astrocytic differentiation pathway. Cell Death Differ 11:196–202

    Article  CAS  PubMed  Google Scholar 

  • Gokhan S, Marin-Husstege M, Yung SY, Fontanez D, Casaccia-Bonnefil P, Mehler M (2005) Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J Neurosci 25:8311–8321

    Article  CAS  PubMed  Google Scholar 

  • Hall SM (1972) The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J Cell Sci 10:535–546

    CAS  PubMed  Google Scholar 

  • Hao Z, Yeung J, Wolf L, Doucette R, Nazarali A (1999) Differential expression of Hoxa-2 protein along the dorsal-ventral axis of the developing and adult mouse spinal cord. Dev Dyn 216:201–217

    Article  CAS  PubMed  Google Scholar 

  • Herndon RM, Price DL, Weiner LP (1977) Regeneration of oligodendroglia during recovery from demyelinating disease. Science 195:693–694

    Article  CAS  PubMed  Google Scholar 

  • Hinks GL, Franklin RJ (2000) Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 16:542–556

    Article  CAS  PubMed  Google Scholar 

  • Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49

    Article  CAS  PubMed  Google Scholar 

  • Islam MS, Tatsumi K, Okuda H, Shiosaka S, Wanaka A (2009) Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions. Neurochem Internat 54:192–198

    Article  CAS  Google Scholar 

  • Jurevics H, Largent C, Hostettler J, Sammond DW, Matsushima GK, Kleindienst A, Toews AD, Morell P (2002) Alterations in metabolism and gene expression in brain regions during cuprizone-induced demyelination and remyelination. J Neurochem 82:126–136

    Article  CAS  PubMed  Google Scholar 

  • Knobler RL, Stempak JG, Laurencin M (1974) Oligodendroglial ensheathment of axons during myelination in the developing rat central nervous system. A serial section electron microscopical study. J Ultrastruct Res 49:34–49

    Article  CAS  PubMed  Google Scholar 

  • Komoly S, Hudson LD, Webster HD, Bondy CA (1992) Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc Natl Acad Sci USA 89:1894–1898

    Article  CAS  PubMed  Google Scholar 

  • Kondo A, Nakano T, Suzuki K (1987) Blood–brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice. Brain Res 425:186–190

    Article  CAS  PubMed  Google Scholar 

  • Lang W, Rodriguez M, Lennon VA, Lampert PW (1984) Demyelination and remyelination in murine viral encephalomyelitis. Ann N Y Acad Sci 436:98–102

    Article  CAS  PubMed  Google Scholar 

  • Labombarda F, González SL, Lima A, Roig P, Guennoun R, Schumacher M, de Nicola AF (2009) Effects of progesterone on oligodendrocyte progenitors, oligodendrocyte transcription factors, and myelin proteins following spinal cord injury. Glia 57:884–897

    Article  PubMed  Google Scholar 

  • Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity. Lab Invest 39:597–612

    CAS  PubMed  Google Scholar 

  • Ludwin SK (1979) An autoradiographic study of cellular proliferation in remyelination of the central nervous system. Am J Pathol 95:683–696

    CAS  PubMed  Google Scholar 

  • Ludwin SK (1980) Chronic demyelination inhibits remyelination in the central nervous system. An analysis of contributing factors. Lab Invest 43:382–387

    CAS  PubMed  Google Scholar 

  • Ludwin SK, Sternberger NH (1984) An immunohistochemical study of myelin proteins during remyelination in the central nervous system. Acta Neuropathol (Berl) 63:240–248

    Article  CAS  Google Scholar 

  • Lyman WD, Brosnan CF, Raine CS (1985) Chronic-relapsing experimental autoimmune encephalomyelitis. Myelin basic protein induces suppression of blastogenesis during remissions but not during exacerbations. J Neuroimmunol 7:345–353

    CAS  PubMed  Google Scholar 

  • Magnus T, Coksaygan T, Korn T, Xue H, Arumugam TV, Mughal MR, Eckley DM, Tang SC, DeTolla L, Rao MS, Cassiani-Ingoni R, Mattson MP (2007) Evidence that nucleocytoplasmic Olig2 translocation mediates brain-injury-induced differentiation of glial precursors to astrocytes. J Neurosci Res 85:2126–2137

    Article  CAS  PubMed  Google Scholar 

  • Mason JL, Xuan S, Dragatsis I, Efstratiadis A, Goldman JE (2003) Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. J Neurosci 23:7710–7718

    CAS  PubMed  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

    CAS  PubMed  Article  Google Scholar 

  • Morell P, Barrett CV, Mason JL, Toews AD, Hostettler JD, Knapp GW, Matsushima GK (1998) Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol Cell Neurosci 12:220–227

    Article  CAS  PubMed  Google Scholar 

  • Nicolay D, Doucette R, Nazarali A (2007) Transcriptional control of oligodendrogenesis. Glia 55:1287–1299

    Article  PubMed  Google Scholar 

  • Noble M (2004) The possible role of myelin destruction as a precipitating event in Alzheimer’s disease. Neurobiol Aging 25:25–31

    Article  CAS  PubMed  Google Scholar 

  • Peters A (2002a) Structural changes that occur during normal aging of primate cerebral hemispheres. Neurosci Biobehav Rev 26:733–741

    Article  PubMed  Google Scholar 

  • Peters A (2002b) The effects of normal aging on myelin and nerve fibers: a review. J Neurocytol 31:581–593

    Article  PubMed  Google Scholar 

  • Peters A, Sethares C (2002) Aging and the myelinated fibers in prefrontal cortex and corpus callosum of the monkey. J Comp Neurol 442:277–291

    Article  PubMed  Google Scholar 

  • Rist JM, Franklin RJ (2008) Taking ageing into account in remyelination-based therapies for multiple sclerosis. J Neurol Sci 274:64–67

    Article  CAS  PubMed  Google Scholar 

  • Rivers LM, Young KM, Rizzi M, Jamen F, Psachoulia K, Wade A, Kessaris N, Richardson WD (2008) PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nature Neurosci 11:1392–1401

    Article  CAS  PubMed  Google Scholar 

  • Sandell JH, Peters A (2002) Effects of age on the glial cells in the rhesus monkey optic nerve. J Comp Neurol 445:13–28

    Article  PubMed  Google Scholar 

  • Setoguchi T, Kondo T (2004) Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation. J Cell Biol 166:963–968

    Article  CAS  PubMed  Google Scholar 

  • Shen S, Sandoval J, Swiss VA, Li J, Dupree J, Franklin RJ, Casaccia-Bonnefil P (2008) Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nature Neurosci 11:1024–1034

    Article  CAS  PubMed  Google Scholar 

  • Sim FJ, Zhao C, Penderis J, Franklin RJ (2002) The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci 22:2451–2459

    CAS  PubMed  Google Scholar 

  • Sloane JA, Hinman JD, Lubonia M, Hollander W, Abraham CR (2003) Age-dependent myelin degeneration and proteolysis of oligodendrocyte proteins is associated with the activation of calpain-1 in the rhesus monkey. J Neurochem 84:157–168

    Article  CAS  PubMed  Google Scholar 

  • Stidworthy MF, Genoud S, Suter U, Mantei N, Franklin RJ (2003) Quantifying the early stages of remyelination following cuprizone-induced demyelination. Brain Pathol 13:329–339

    PubMed  Google Scholar 

  • Sun T, Dong H, Wu L, Kane M, Rowitch DH, Stiles CD (2003) Cross-repressive interaction of the Olig2 and Nkx2.2 transcription factors in developing neural tube associated with formation of a specific physical complex. J Neurosci 23:9547–9556

    CAS  PubMed  Google Scholar 

  • Tochitani S, Hayashizaki Y (2008) Nkx2.2 antisense RNA overexpression enhanced oligodendrocytic differentiation. Biochem Biophys Res Commun 372:691–696

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Hadzic T, Nishiyama A (2004) Transient upregulation of Nkx2.2 expression in oligodendrocyte lineage cells during remyelination. Glia 46:311–322

    Article  PubMed  Google Scholar 

  • Wegner M (2000a) Transcriptional control in myelinating glia: flavors and spices. Glia 31:1–14

    Article  CAS  PubMed  Google Scholar 

  • Wegner M (2000b) Transcriptional control in myelinating glia: the basic recipe. Glia 29:118–123

    Article  CAS  PubMed  Google Scholar 

  • Wegner M (2001) Expression of transcription factors during oligodendroglial development. Microsc Res Tech 52:746–752

    Article  CAS  PubMed  Google Scholar 

  • Wei Q, Miskimins WK, Miskimins R (2005) Stage-specific expression of myelin basic protein in oligodendrocytes involves Nkx2.2-mediated repression that is relieved by the Sp1 transcription factor. J Biol Chem 280:16284–16294

    Article  CAS  PubMed  Google Scholar 

  • Yajima K, Suzuki K (1979) Ultrastructural changes of oligodendroglia and myelin sheaths induced by ethidium bromide. Neuropathol Appl Neurobiol 5:49–62

    Article  CAS  PubMed  Google Scholar 

  • Zeller NK, Behar TN, Dubois-Dalcq ME, Lazzarini RA (1985) The timely expression of myelin basic protein gene in cultured rat brain oligodendrocytes is independent of continuous neuronal influences. J Neurosci 5:2955–2962

    CAS  PubMed  Google Scholar 

  • Zhao J-W, Raha-Chowdhury R, Fawcett JW, Watts C (2009) Astrocytes and oligodendrocytes can be generated from NG2 + progenitors after acute brain injury: intracellular localization of oligodendrocyte transcription factor 2 is associated with their fate choice. Eur J Neurosci 29:1853–1869

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This project was supported by an operating grant from the Canadian Institutes of Health Research (to AN and RD) and by a Pilot Project Grant from the Cameco Multiple Sclerosis Neuroscience Research Center (to RD and AN). We thank Dr. Collette Wheeler and Ms. Michele Moroz for their assistance and guidance in monitoring the health status of the mice. Special thanks are also due to R. Sobchishin and M. Basiri for technical assistance. We are also grateful to Drs. M. Gardinier and H. Takebayashi for providing the mouse monoclonal antibody to MOG and the rabbit polycolonal antibody to Olig2, respectively.

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada

    J. Ronald Doucette

  2. Cameco MS Neuroscience Research Center, City Hospital, Saskatoon, SK, S7K 0M7, Canada

    J. Ronald Doucette & Adil J. Nazarali

  3. Laboratory of Molecular Biology, College of Pharmacy and Nutrition, 116 Thorvaldson Building, 110 Science Place, University of Saskatchewan, Saskatoon, SK, S7N 5C9, Canada

    Rubin Jiao & Adil J. Nazarali

Authors
  1. J. Ronald Doucette
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rubin Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adil J. Nazarali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adil J. Nazarali.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ronald Doucette, J., Jiao, R. & Nazarali, A.J. Age-Related and Cuprizone-Induced Changes in Myelin and Transcription Factor Gene Expression and in Oligodendrocyte Cell Densities in the Rostral Corpus Callosum of Mice. Cell Mol Neurobiol 30, 607–629 (2010). https://doi.org/10.1007/s10571-009-9486-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-009-9486-z

Keywords

  • Aging
  • Astrocytes
  • Myelin
  • Oligodendrocytes
  • Olig2
  • Nkx2.2
  • PDGFαR
  • MOG
  • MBP