Show simple item record

dc.creatorPacholko, Anthony G
dc.date.accessioned2019-08-02T14:27:20Z
dc.date.available2019-08-02T14:27:20Z
dc.date.created2019-11
dc.date.issued2019-08-02
dc.date.submittedNovember 2019
dc.identifier.urihttp://hdl.handle.net/10388/12238
dc.description.abstractAlzheimer’s disease (AD) incidence is expected to double by 2038. This coincides with similar trends in obesity and chronic inflammation. It is known that insulin resistant and chronic inflammatory conditions can increase the risk of AD-like neurodegeneration, likely through mechanisms involving induction of brain insulin resistance. Insulin resistant brain states are associated with increased activity of glycogen synthase kinase-3β (GSK-3β), whose constitutive activity is inhibited, in part, by activity within the insulin pathway. Aberrant GSK-3β signaling contributes to increased amyloid-β production (senile plaques) and Tau protein hyperphosphorylation (neurofibrillary tangles), hallmarks of AD-like neurodegeneration. In addition, nearly two-thirds of AD patients are female, which strongly suggests a role for the post-menopausal loss of the female sex hormone, estrogen, in the pathogenic events associated with AD. Estrogen is known to diminish neurodegenerative processes, such as β-amyloidopathy, mitochondrial dysfunction and oxidative stress, in a variety of animal models. A reduction in estrogen levels following menopause has also been associated with increased risk of insulin resistance and inflammation, thus necessitating exploration of the neurodegenerative potential of these conditions in a female animal model. As a first step, by combining a high-sucrose diet (20% of the drinking water) with intraperitoneal LPS injections (0.1 mg/kg; once/month for 3 months) over seven months in reproductively normal female wild-type mice (C57Bl/6; n=10/group), a protective effect of low-dose LPS on high-sucrose diet-induced pathology was demonstrated. Results from the high-sucrose group confirmed that a high-sucrose diet is a suitable model of neurodegeneration, as evidenced by exaggerated glucocorticoid expression, spatial learning deficits, irregularities within the insulin pathway, and increased β-amyloid production and Tau phosphorylation. Interestingly, while LPS had little to no effect in isolation, it exerted a protective influence when added to animals sustained on a high-sucrose diet. Corticosterone homeostasis, Aβ and pTau levels, and insulin pathway second messenger expression were all rescued following addition of LPS. Given the hypothesized role of increased GSK-3β activity in neurodegeneration, mice following the combined treatment regimen were supplemented with lithium orotate (1 mg/L in the drinking water), a potent inhibitor of GSK-3β, to assess its prophylactic potential against dietary- and-inflammatory insult-mediated neurodegeneration. As the addition of LPS to animals on a high-sucrose diet proved to be protective rather than aggravating, I was unable to assess lithium for prophylaxis against neurodegeneration. However, antagonistic interactions between LPS and lithium were observed (lithium blocked the effects of LPS). When added to mice following the combined regimen, lithium returned corticosterone and Aβ levels to those observed in animals sustained on high-sucrose alone, while completely abolishing spatial learning deficits and anxiety-like behavior. To sum, the work presented confirms a 1) high-sucrose diet as a model of neurodegeneration, 2) supports a protective role for transient inflammation against dietary-insult, and 3) suggests an antagonistic interaction between lithium and LPS.
dc.format.mimetypeapplication/pdf
dc.subjectNeurodegeneration
dc.subjectInsulin Resistance
dc.subjectInflammation
dc.subjectLithium
dc.titleEffects of a high-sucrose diet and systemic inflammation on Alzheimer’s disease-related processes in reproductively normal female wild-type mice
dc.typeThesis
dc.date.updated2019-08-02T14:27:20Z
thesis.degree.departmentPharmacology
thesis.degree.disciplinePharmacology
thesis.degree.grantorUniversity of Saskatchewan
thesis.degree.levelMasters
thesis.degree.nameMaster of Science (M.Sc.)
dc.type.materialtext
dc.contributor.committeeMemberMousseau, Darrell D
dc.contributor.committeeMemberTaghibiglou, Changiz
dc.contributor.committeeMemberDesai, Kaushik
dc.contributor.committeeMemberZhang, Yanbo
dc.creator.orcid0000-0002-7832-254X


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record