Schwann cell remyelination is not replaced by oligodendrocyte remyelination following ethidium bromide induced demyelination

Demyelinated CNS axons can be remyelinated by Schwann cells. A recent study concluded that with time Schwann cell remyelination is replaced by oligodendrocyte remyelination [9]. To examine this, the extent of Schwann cell and oligodendrocyte remyelination at 4, 6.5 and 24 weeks was determined for ethidium bromide lesions made in the spinal cords of rats. Although the extent of oligoden-drocyte remyelination increased with time there was no significant change in the amount of Schwann cell remyelination. This indicates that Schwann cell remyelination is stable and is not replaced by oligodendrocyte remyelination.     

Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression

Although macrophages are mediators of CNS demyelination, they are also implicated in remyelination. To examine the role of macrophages in CNS remyelination, adult rats were depleted of monocytes using clodronate liposomes and demyelination induced in the spinal cord white matter using lysolecithin. In situ hybridization for scavenger receptor-B and myelin basic protein (MBP) revealed a transiently impaired macrophage response associated with delayed remyelination in liposome-treated animals. Macrophage reduction corresponded with delayed recruitment of PDGFRalpha+ oligodendrocyte progenitor cells (OPCs), which preceded changes in myelin phagocytosis, indicating a macrophage effect on OPCs independent of myelin debris clearance. Macrophage-depletion induced changes in the mRNA expression of insulin-like growth factor-1 and transforming growth factor beta1, but not platelet-derived growth factor-A and fibroblast growth factor-2. These data suggest that the macrophage response to toxin-induced demyelination influences the growth factor environment, thereby affecting the behavior of OPCs and hence the efficiency of remyelination.     

Gas6-Tyro3 signaling is required for Schwann cell myelination and possible remyelination

正Myelin plays important roles in vertebrates,ensuring the rapid propagation of action potentials and the long-term integrity of axons,but the molecular mechanisms of myelin formation remain poorly understood.Recent studies have demonstrated that myelination is regulated by the TYRO3,AXL(also known as UFO)and MERTK     

Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes during CNS remyelination

During normal brain development, axons are myelinated by mature oligodendrocytes (OLGs). Under pathological, demyelinating conditions within the central nervous system (CNS), axonal remyelination is only partially successful because oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated state resulting in a failure to generate myelinating OLGs. Tissue Transglutaminase (TG2) is a multifunctional enzyme, which amongst other functions, is involved in cell differentiation. Therefore, we hypothesized that TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates remyelination. In vivo studies, using the cuprizone model for de- and remyelination in TG2(-/-) and wild-type mice, showed that during remyelination expression of proteolipid protein mRNA, as a marker for remyelination, in the corpus callosum lags behind in TG2(-/-) mice resulting in less myelin formation and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies showed that rat OPCs express TG2 protein and activity which reduces when the cells have matured into OLGs. Furthermore, when TG2 activity is pharmacologically inhibited, the differentiation of OPCs into myelin-forming OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in remyelination of the CNS, probably through stimulating OPC differentiation into myelin-forming OLGs. Therefore, manipulating TG2 activity may represent an interesting new target for remyelination in demyelinating diseases.     

Schwann cell proliferation during Wallerian degeneration is not necessary for regeneration and remyelination of the peripheral nerves: axon-dependent removal of newly generated Schwann cells by apoptosis

Peripheral nerve injury is followed by a wave of Schwann cell proliferation in the distal nerve stumps. To resolve the role of Schwann cell proliferation during functional recovery of the injured nerves, we used a mouse model in which injury-induced Schwann cell mitotic response is ablated via targeted disruption of cyclin D1. In the absence of distal Schwann cell proliferation, axonal regeneration and myelination occur normally in the mutant mice and functional recovery of injured nerves is achieved. This is enabled by pre-existing Schwann cells in the distal stump that persist but do not divide. On the other hand, in the wild type littermates, newly generated Schwann cells of injured nerves are culled by apoptosis. As a result, distal Schwann cell numbers in wild type and cyclin D1 null mice converge to equivalence in regenerated nerves. Therefore, distal Schwann cell proliferation is not required for functional recovery of injured nerves.     

Increasing local levels of IGF-I mRNA expression using adenoviral vectors does not alter oligodendrocyte remyelination in the CNS of aged rats

IGF-I, a growth factor that contributes to developmental myelination, shows increased levels of expression within experimental models of remyelination. The pattern of IGF-I mRNA expression changes with the rate of remyelination, with peak levels of expression occurring earlier during rapid remyelination in young adult rats compared to the slower remyelination in old adult rats. In this study we have attempted to accelerate remyelination in old adult rats by using an IGF-expressing adenoviral vector (IGF-I-Ad) to bring forward the timing of peak level of IGF-I expression. Following injection of IGF-I-Ad into focal areas of lysolecithin-induced demyelination in the spinal white matter of old adult rats we created levels of IGF-I mRNA expression at 10 days that were considerably higher than those normally occurring at this time and more similar to those in young animals. However, despite the elevated levels of IGF-I mRNA expression there was no significant change in the extent of oligodendrocyte remyelination compared to saline controls or animals injected with an adenoviral vector expressing LacZ (NT-LacZ-Ad). There was a small increase in Schwann cell remyelination in IGF-I-Ad- and NT-LacZ-Ad-injected animals compared to saline controls. These results indicate that changing the levels of IGF-I directly within demyelinating lesions undergoing remyelination is not sufficient to alter remyelination and that the proremyelinating effects of systemically delivered IGF-I are unlikely to be due to direct effects on the oligodendrocyte lineage.     

HLA-A2 homozygosity but not heterozygosity is associated with Alzheimer disease

AD is associated with the A2 allele of the human leukocyte antigen (HLA). However, it is not currently known whether there is any difference between A2 homozygotes and A2 heterozygotes. The authors studied 458 patients with AD and found that A2 homozygotes had earlier onset of AD than either A2 heterozygotes (5.4 years, p = 0.002) or those without A2 (5.2 years, p = 0.003). The "recessive" nature of this association suggests that loss of function at the HLA-A locus or a closely linked gene is associated with AD.     

Type 1 astrocytes fail to inhibit Schwann cell remyelination of CNS axons in the absence of cells of the O-2A lineage.

The extent to which Schwann cells are able to remyelinate demyelinated CNS axons is influenced by the presence of astrocytes. In order to study further the nature of astrocyte control of Schwann cell remyelination in the CNS, cultures containing type 1 astrocytes and a small proportion of Schwann cells, but depleted of O-2A lineage cells by exposure to cytosine arabinoside and complement-mediated immunocytolysis, were transplanted into glial-free lesions in adult rat spinal cord in which the host response to demyelinated axons was suppressed by X-irradiation. Following transplantation of these O-2A lineage-depleted cultures into X-irradiated, demyelinating lesions, there was extensive remyelination of demyelinated axons by Schwann cells, a result which contrasted with those obtained from earlier experiments in which O-2A lineage cells were present within the transplant, and/or recruited from host tissue. This experiment shows that the presence of O-2A lineage cells is required in order for transplanted type 1 astrocytes to organise in a manner which inhibits extensive Schwann cell remyelination of CNS axons.     

Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy

Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.     

Neuregulin 1 growth factors regulate proliferation but not apoptosis of a CNS neuronal progenitor cell line

Growth factor-dependent proliferation of neuronal progenitors is an essential stage in CNS development. Although several of these growth factors have been identified, high levels of neuregulin 1 (NRG1) mRNA and protein expression in the CNS during the time of neuronal progenitor expansion suggest NRG1 growth factors may also play a key role in their proliferation. No previous studies have examined the expression of multiple NRG1 isoforms and receptors in these progenitors and their role in proliferation or apoptosis. Using a rat CNS clonal cell line with neuronal progenitor properties, we show for the first time these cells coexpress multiple NRG1 isoforms (NRGbeta1, NRGbeta3, CRD-NRGbeta, and SMDF, but not GGF2 or any alpha isoforms) and all three cognate receptors (erbB2-4). We also show for the first time the presence of mRNA for all four variants of the erbB4 receptor in a single CNS cell type. Neutralizing antibody treatments suggest NRG1 isoforms and receptors are involved in proliferation but not apoptosis of these cells. This model system should be useful in future studies of the ligand specificity and function(s) of the erbB4 receptor variants.