The effect of aging on myelinating gene expression and oligodendrocyte cell densities

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, I 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 (RCC) of mice, which enabled me 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. I 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 RCC of both control mice and mice recovering from cuprizone-induced demyelination. My results also show there was an age-related impaired recruitment of progenitor cells to replace lost OLs even though there was no major age-related decrease in the size of the progenitor cell pool (PDGF á R+ve/GFAP-ve, and Olig2Nuc+ve/PDGFáR+ve cells). However, there were cuprizone-induced increased numbers of astrocyte progenitor cells (Olig2Cyto+ve/PDGFáR+ve) in these same mice; thus PDGFáR+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 PDGFáR+ve progenitor cells into OLs and astrocytes and lead me to suggest that during aging there must be a transcriptional switch mechanism in the progenitor cell fate choice in favour of astrocytes. This may at least partially explain the age-related decrease in efficiency of OL myelination and remyelination.