Multiple sclerosis (MS) is a neurodegenerative disorder characterized by CNS inflammation and axonal demyelination. In addition, axonal pathology has also been reported in MS and may be responsible for the functional deficits associated with this disease. Based on preliminary data from our laboratory, we propose that a specific domain of the neuron, known as the axon initial segment (AIS), is targeted in MS. Consistent with our work from the human tissue, we have also observed disruption of AIS integrity in a murine CNS inflammatory model and observations strongly implicate reactive microglia as mediators of AIS disruption. In contrast, a murine model of demyelination did not exhibit AIS pathology but reactive microglia were prevalent. Since we propose that reactive microglia drive AIS disruption in our inflammatory CNS model but observe no AIS pathology following demyelination even in the presence of reactive microglia, we propose that reactive microglia in these models exhibit different interactions and molecular profiles. To test this hypothesis, we employed immunofluorescence labeling combined with confocal microscopy to quantify microglia reactivity and microglia-AIS interaction. Additionally, we conducted a microarray using RNA isolated from microglia from both the inflammatory and demyelinating models. Our findings show that microglia are reactive prior to pathology in both models and that the extent of AIS-microglial contact is similar between the models but significantly increased as compared to naïve mice. Our microarray data reveal a substantial difference in gene expression indicating functional differences between the reactive microglia in the inflammatory and demyelinating models. Finally, following functional enrichment analysis of microarray data, the complement pathway emerged as a potential contributor to the AIS pathology observed in EAE.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5284 |
| Date | 01 January 2016 |
| Creators | Hartley, Rebecca K |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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