Biomedical subjects

Fraser J Sim

Publications and source records attributed to Fraser J Sim.

3 recordsLinked to original sources

PubMed2002

Ageing and CNS remyelination.

Remyelination of demyelinated axons in the CNS is a regenerative process that, like many others, becomes less efficient with age. This article reviews a series of studies in which toxin models of demyelination have been used to characterize this phenomenon. The delayed rate of remyelination in older animals is associated with a decrease in the rate of oligodendrocyte progenitor recruitment and in the rate at which the recruited cells differentiate into remyelinating oligodendrocytes. The differences in the behaviour of oligodendrocyte lineage cells during remyelination in young and old animals are related to the age-related changes that occur in the expression of growth factors that affect the proliferation, migration and differentiation of oligodendrocyte progenitors, and in the inflammatory process associated with toxin-induced demyelination. Based on these differences, a conceptual framework is proposed to explain the age-associated effects on remyelination, which we have called the dysregulation hypothesis, and the feasibility of reversing these effects is discussed.

Aging↗

PubMed2002

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.

Age Factors↗

PubMed2002

Expression of the POU-domain transcription factors SCIP/Oct-6 and Brn-2 is associated with Schwann cell but not oligodendrocyte remyelination of the CNS.

The class III POU-domain transcription factor SCIP/Oct-6 is expressed by promyelinating Schwann cells and, in tissue culture, by oligodendrocyte progenitors (OPs), but is down-regulated in both cells types as they differentiate. Although the expression of SCIP/Oct-6 has been examined in peripheral nerve remyelination, its expression in CNS remyelination has not been addressed. Using a toxin model of demyelination, in which the demyelinated axons are remyelinated in an age-dependent manner by both oligodendrocytes and Schwann cells, we have compared the expression of SCIP/Oct-6 mRNA with that of an OP marker (PDGF-alphaR), a marker of myelinating oligodendrocytes (PLP), and markers of myelinating Schwann cells (P(0) and Krox-20) by in situ hybridization. We have found that the expression of SCIP/Oct-6 mRNA precedes that of P(0) and Krox-20 mRNA expression, but bears little correlation with the expression profiles of either PDGF-alphaR or PLP mRNA. Moreover, there is a spatial correlation between the expression SCIP/Oct-6 mRNA and that of P(0) but not of PDGF-alphaR. These results indicate that SCIP/Oct-6 expression following CNS demyelination is associated with Schwann cell and not oligodendrocyte remyelination. We have also shown that another POU-domain transcription factor, Brn-2, is expressed during CNS remyelination, but that like SCIP/Oct-6, it too has an expression profile indicating that it is associated with the Schwann cell component of remyelination. In addition, we show that Brn-2 expression in Schwann cells is not restricted to CNS remyelination but is also expressed in a similar manner to SCIP/Oct-6 during Schwann cell myelination of neonatal peripheral nerves and regenerating transected adult nerve and in cultured Schwann cells following induction of elevated cAMP levels.

Animals↗