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Investigating Axon-Glia Interactions in Inflammatory Demyelination and Myelin Repair
Abstract
Multiple Sclerosis (MS) is one of the most debilitating autoimmune inflammatory disorders of the central nervous system (CNS). It is characterized by inflammatory demyelinating CNS lesions leading to profound physical and neurological defects. This project seeks to investigate axon-glia interactions in inflammatory demyelination and myelin repair using the experimental autoimmune encephalomyelitis (EAE). In this study, I examined glial cell inflammatory response and oligodendrocyte axon interactions in acute and chronic EAE disease paradigms. EAE was induced in two transgenic mouse lines: (1) CNP:m-EGFP and (2) Aldh1L1CreERT2:Ai14 to directly visualize (1) myelin sheath membrane and (2) astrocytes in their cellular entirety in the EAE model.
We assessed glial cell proliferation from EAE disease onset until peak disease by administering five daily doses of 5-ethynyl-2'-deoxyuridine (EdU) during this critical rising phase. Immunohistochemical microscopy analysis of EdU labeled cells revealed robust oligodendrocyte precursor cell (OPC) proliferation in response to inflammatory demyelination. Moreover, some of the newly generated OPCs differentiated into mature myelinating oligodendrocytes, synthesizing new myelin sheath, and ensheathing denuded axons as early as five days post disease onset. While OPCs and mature oligodendrocytes were generated in the acute autoimmune demyelination phase, most of them were lost by the late chronic stages of EAE disease. We further investigated oligodendrocyte-axon interactions during EAE and found that newly generated myelin sheath membranes are often associated with loosely packed paranodal protein caspr. Together, our results provide new insight into myelin disruption and regeneration, and may open up potential avenues to accelerate remyelination and allow efficient repair.
Citation
Sheth, Pari (2022). Investigating Axon-Glia Interactions in Inflammatory Demyelination and Myelin Repair. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /198101.