Aging exacerbates myelin disruption and axon injury following demyelination

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dc.contributor.advisorYong, Voon Wee
dc.contributor.authorMichaels, Nathan J.
dc.contributor.committeememberOusman, Shalina S.
dc.contributor.committeememberCasha, Steven
dc.date2019-06
dc.date.accessioned2019-05-03T17:14:15Z
dc.date.available2019-05-03T17:14:15Z
dc.date.issued2019-04-30
dc.description.abstractFor 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.en_US
dc.identifier.citationMichaels, 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.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/36466
dc.identifier.urihttp://hdl.handle.net/1880/110284
dc.language.isoengen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectdemyelinationen_US
dc.subjectmultiple sclerosisen_US
dc.subjectNADPH oxidaseen_US
dc.subjectmicrogliaen_US
dc.subjectneuroprotectionen_US
dc.subject.classificationNeuroscienceen_US
dc.titleAging exacerbates myelin disruption and axon injury following demyelinationen_US
dc.typedoctoral thesisen_US
thesis.degree.disciplineMedicine – Neuroscienceen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameDoctor of Philosophy (PhD)en_US
ucalgary.item.requestcopytrue
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