Aging exacerbates myelin disruption and axon injury following demyelination
Date
2019-04-30
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Abstract
For the majority of individuals with multiple sclerosis, the disease begins with a relapsing-remitting disease course that transitions to secondary progressive multiple sclerosis. Population-based studies have identified age as a critical risk factor for this transition. The mechanisms linking age and progressive multiple sclerosis remain poorly understood. Studies in animal models of demyelination suggest age is associated with increased axon injury and loss. Despite these findings, how several features and mechanisms of lesion development in the spinal cord white matter differ between young and aging animals are unclear. In this thesis, I characterized the early events of lesion formation in young and middle-aged animals, focusing particularly on axon injury/loss, oligodendrocyte lineage cell loss, and myelin disruption. I used an unbiased, RNA sequencing approach to explore the mechanisms underlying age-exacerbated injury. I used differential gene expression and pathway analysis data acquired from RNA sequencing to hypothesize that reactive oxygen species derived from NADPH oxidase is associated with elevated myelin and axon damage in middle-aged animals. I then used a transgenic mouse approach to differentiate between microglia and infiltrating peripheral myeloid cells in the spinal cord and found gp91phox, the catalytic subunit of NADPH oxidase, was primarily expressed in microglia and its expression was elevated in middle-aged microglia. Lastly, I tested the ability of indapamide, a generic medication with antioxidant properties, to ameliorate age-exacerbated myelin and axon loss in vivo, and to scavenge reactive oxygen species derived from microglia in vitro. Indapamide attenuated the degree of myelin disruption and axon loss, decreased lipid peroxidation in the spinal cord white matter, and reduced extracellular superoxide produced by microglia.
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Keywords
demyelination, multiple sclerosis, NADPH oxidase, microglia, neuroprotection
Citation
Michaels, N. J. (2019). Aging exacerbates myelin disruption and axon injury following demyelination (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.