The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation.
The age-associated decrease in the efficiency of CNS remyelination has clear implications for recovery from demyelinating diseases such as multiple sclerosis (MS) that may last for several decades. Developing strategies to reverse the age-associated decline requires the identification of how the regenerative process is impaired. We addressed whether remyelination becomes slower because of an impairment of recruitment of oligodendrocyte progenitors (OPs) or, as is the case in some MS lesions, an impairment of OP differentiation into remyelinating oligodendrocytes. The OP response during remyelination of focal, toxin-induced CNS demyelination in young and old rats was compared by in situ hybridization using probes to two OP-expressed mRNA species: platelet-derived growth factor-alpha receptor and the OP transcription factor myelin transcription factor 1 (MyT1). We found that the expression patterns for the two OP markers are very similar and reveal a delay in the colonization of the demyelinated focus with OPs in the old animals compared with the young animals. By comparing the mRNA expression pattern of MyT1 with that of the myelin proteins myelin basic protein and Gtx, we found that in the old animals there is also a delay in OP differentiation that increases with longer survival times. These results indicate that the age-associated decrease in remyelination efficiency occurs because of an impairment of OP recruitment and the subsequent differentiation of the OPs into remyelinating oligodendrocytes, and that strategies aimed at ameliorating the age-associated decline in remyelination efficiency will therefore need to promote both components of the regenerative process.
Sim
Fraser J
FJ
Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom.
Zhao
Chao
C
Penderis
Jacques
J
Franklin
Robin J M
RJ
D000367:Age Factors; D000375:Aging / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology*; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004996:Ethidium; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology*; D009836:Oligodendroglia / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; C117745:Nkx6-2 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; C490680:Myt1 kinase, rat; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D017346:Protein Serine-Threonine Kinases; D004996:Ethidium