ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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Description
Alzheimer’s disease (AD) is characterized by the degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the majority of cholinergic input to the cortical mantle and together form the basocortical cholinergic system. Histone deacetylase (HDAC) dysregulation in the temporal lobe has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in cortical and cortically-projecting cholinergic nbM neuronal degeneration during AD onset is unknown. In an effort to characterize alterations in the basocortical epigenome semi-quantitative western blotting and immunohistochemistry were utilized to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), or severe AD (sAD). In the frontal cortex, immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD. Cortical HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in prodromal and mild AD compared to aged cognitively normal controls. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to controls. Basal forebrain levels of HDAC1, 3, 4, 6 and SIRT1 were stable across disease progression, while HDAC2 levels were significantly decreased in sAD. Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei immunoreactive for the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3, and Thioflavin-S, a marker of mature neurofibrillary tangles (NFTs). HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages, and was exacerbated in tangle-bearing cholinergic nbM neurons. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. These findings identify global HDAC and SIRT alterations in the cortex while HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction and NFT pathology during the progression of AD.
ContributorsMahady, Laura Jean (Author) / Mufson, Elliott J (Thesis advisor) / Bimonte-Nelson, Heather A. (Thesis advisor) / Coleman, Paul (Committee member) / Bowser, Robert (Committee member) / Arizona State University (Publisher)
Created2018
Description
Variations in menopause etiologies, from surgical manipulation to a natural transition, can impact cognition in both healthy and neurodegenerative aging. Although abundant research has demonstrated impacts from surgical versus transitional menopause, such as variations in timing of menopause, both variations in initiation of menopause and length of time since menopause, but not all avenues have been systematically evaluated. Further, assessments of variations in hormone therapies have demonstrated marked outcomes on the brain and cognition in different menopause etiologies, and results can differ depending on type of hormone, combination of hormones, dose, route of administration, among other factors, in regard to healthy aging. Further, the impact of the endocrine system on neurodegenerative disease is multifaceted. Research has highlighted that the endocrine system not only impacts neurodegeneration, such as in Alzheimer’s disease (AD), but that fluctuations in the endocrine system might be strong mediators in disease prevalence and progression. This dissertation seeks to understand how factors such as menopause etiology, biological sex, and hormone therapy impact normative and neurodegenerative aging. Assessments in a rat model of normal aging of progestogen-based hormone therapy given during the transition to menopause demonstrated attenuation of impairment seen with transitional menopause that was working memory specific. In evaluating a rat model of AD, there were distinct trends in neuropathology and associated cognitive changes in males and females with and without gonadal hormone deprivation. Further, assessment of transitional menopause in this AD model yielded an interaction between follicular depletion and genotype for neuropathology that was not present in cognitive assessments. Together, these dissertation chapters highlight that there are a multitude of factors to consider when evaluating effects of menopause and that these variations in experience underscore a need for personalized medicine when selecting therapeutic targets for healthy and neurodegenerative aging that includes consideration of overall hormone milieu and menopause history. Further, these data suggest that the inclusion of males and females in the study of AD-related factors is crucial for understanding disease progression.
ContributorsPena, Veronica L (Author) / Bimonte-Nelson, Heather A (Thesis advisor) / Conrad, Cheryl D (Committee member) / Coleman, Paul (Committee member) / Sanabria, Federico (Committee member) / Arizona State University (Publisher)
Created2023