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Precursor cells have the capacity to repopulate the demyelinated brain, but the molecular mechanisms that facilitate their recruitment are largely unknown. The low-affinity neurotrophin receptor, p75(NTR), may be one of these regulators; however, its expression profile by oligodendroglia within the multiple sclerosis (MS) brain remains uncertain. We therefore assessed the expression profile of this receptor within 8 MS and 4 control brains. We found no evidence of expression of p75(NTR) by mature oligodendrocytes. Instead, we demonstrated the presence of p75(NTR) on a subgroup of NG2-positive oligodendroglial progenitors in a periventricular plaque in one MS sample. Notably, p75(NTR)-expressing cells were also detected within the subventricular zone (SVZ) of this brain, adjacent to the periventricular plaque. In animals with experimental demyelination we observed similar patterns of p75(NTR) expression, initially confined to precursor cells within the SVZ, followed at later stages in the disease course by its expression amongst a subset of oligodendroglial progenitors within the corpus callosum. These data suggest that a population of precursor cells within the SVZ can be induced to express p75(NTR) and to subsequently assume an oligodendroglial progenitor phenotype in response to demyelination in the adjacent white matter.

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.

The low affinity neurotrophin receptor (p75(NTR)) is implicated in promoting oligodendrocytic death after nerve growth factor (NGF) stimulation but NGF and neurotrophin-3 (NT-3) can also potentiate oligodendrocytic survival. We show regional variability in p75(NTR) expression within the central nervous system of the postnatal rat; expression is readily detectable by immunohistochemistry upon a subset of CNPase-positive oligodendroglia in optic nerve but not within the cerebrum. Nevertheless, oligodendroglia isolated from the cerebrum and cultured for 16 hours express p75(NTR) as well as the trkC but not the TrkA gene. Viability was not, however, influenced by exposure to either NGF or NT-3. Cells overexpressing p75(NTR) remained unresponsive to NGF but exhibited potentiated survival with NT-3, correlating with the differential expression profile of their high affinity receptors.

The cytoplasmic juxtamembrane region of the p75 neurotrophin receptor (p75(NTR)) has been found to be necessary and sufficient to initiate neural cell death. The region was named "Chopper" to distinguish it from CD95-like death domains. A 29-amino acid peptide corresponding to the Chopper region induced caspase- and calpain-mediated death in a variety of neural and non-neural cell types and was not inhibited by signaling through Trk (unlike killing by full-length p75(NTR)). Chopper triggered cell death only when bound to the plasma membrane by a lipid anchor, whereas non-anchored Chopper acted in a dominant-negative manner, blocking p75(NTR)-mediated death both in vitro and in vivo. Removal of the ectodomain of p75(NTR) increased the potency of Chopper activity, suggesting that it regulates the association of Chopper with downstream signaling proteins.