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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

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.

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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.

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Correspondence to Adil J. Nazarali.

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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

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

Keywords

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