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- Member of: ASU Electronic Theses and Dissertations
Description
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases worldwide, with no effective treatments or preventions. Evidence suggests that environmental factors, including dietary nutrients, contribute to the etiology of AD. Choline is an essential nutrient found in many common foods. Choline is produced endogenously, but not at levels sufficient for healthy metabolic function and thus requires dietary supplementation. Literature shows that ~90% of Americans do not meet the adequate intake threshold for dietary choline consumption and therefore are dietary choline-deficient. While dietary choline supplementation throughout life has been shown to have significant health benefits, such as reducing AD pathology and improving cognition in a mouse model of AD, the impacts of dietary choline deficiency are unknown. Experiments were designed to understand the effects of dietary choline deficiency in healthy, non-transgenic mice (NonTg) and in the 3xTg-AD mouse model of AD. From 3 to 12 months of age, mice received either adequate choline (ChN) in the diet or were put on a choline-deficient (Ch-) diet. A Ch- diet leads to significant weight gain throughout life in both the NonTg and 3xTg-AD mice, with AD mice showing a greater increase. Additionally, impaired glucose metabolism, which is a risk factor for AD, was induced in both NonTg Ch- and 3xTg-AD Ch- mice. Interestingly, Ch- induced cardiomegaly in 3xTg-AD mice and elevated markers of cardiac dysfunction in NonTg mice to similar levels in 3xTg-AD mice. Finally, Ch- exacerbated amyloid-β plaque pathology and tau hyperphosphorylation in the hippocampus and cortex of 3xTg-AD mice. Proteomic analyses revealed Ch- induced changes in hippocampal proteins associated with postsynaptic receptor regulation, microtubule stabilization, and neuronal development, as well as well-known AD-associated proteins (MAPT, BACE1, MECP2, CREBBP). Proteomic analyses also revealed Ch- induced changes of plasma proteins associated with secondary pathologies of AD including inflammation, immune response insulin metabolism, and mitochondrial dysfunction (SAA1, SAA2, IDE, HSPD1, VDAC-1, VDACE-2). Taken together, these data suggest that dietary choline deficiency induces system-wide cellular and molecular dysfunction associated with AD across several pathogenic axes, through proteomic changes not only in the hippocampus but also in the plasma.
ContributorsDave, Nikhil (Author) / Velazquez, Ramon (Thesis advisor) / Piras, Ignazio (Committee member) / Mastroeni, Diego (Committee member) / Arizona State University (Publisher)
Created2022
Description
Alzheimer’s Disease (AD) is one of the most common forms of dementia and a major cause of disability and dependency in older patients worldwide.Although there has been a lot of research done in the field of gene expression and possible drivers of AD, there has not been enough investigation into transcription start site and alternative promoter usage of AD.
With relatively small genomes, species have evolved mechanisms for diversifying their transcriptome, which is the set of messenger mRNA transcripts produced in a given cell.
While the most well-known mechanism of diversification is alternative splicing, another mechanism that has been less explored is alternative promoter (AP) usage, which generates different transcripts by selecting different transcription start sites (TSSs) upstream of a gene.
More importantly, AP usage can bring about different coding sequences, which can in some cases lead to changes within the N-termini of the cognate proteins.
Alternative promoter usage has the potential to regulate processes like alternative splicing, tissue specificity, regional specificity and subcellular specificity of gene expression and gene activation during development.
In this study a customized pipeline for STRIPE-seq generated data was applied to AD and control data set and the first AD promoter atlas was generated.
This atlas was used to generate list of genes with differentially used TSRs and biological pathways they are involved in.
Finally, a consensus cluster set was created to investigate alternative promoter usage in AD patients and alternative promoter usage was shown in Alzheimer’s Disease related genes such as APOE and MAPT.
ContributorsStampar, Mojca (Author) / Lee, Heewook (Thesis advisor) / Raborn, Randolph T (Committee member) / Mastroeni, Diego (Committee member) / Arizona State University (Publisher)
Created2022
Description
Frontotemporal dementia (FTD) is a neurodegenerative disease that causes deterioration of the frontal and temporal lobe. Detection is pivotal in preventative care, but current screening methods are not sensitive enough to detect early-stage disease. Synapse loss has been implicated as an early contributor to neurodegeneration and subsequent atrophy. Fluorine-18 fluorodeoxy-glucose (18[F]-FDG) positron emission tomography (PET) is a noninvasive imaging biomarker method frequently used as a surrogate measure for synaptic activity in the brain. PET scans using 18[F]-FDG tracers were performed on progranulin (GRN) knockout mice (Grn-/-), a commonly used mouse model of FTD. Interestingly, 18[F]-FDG PET at both, 9 months and 11 months, two time points considered early symptomatic in the Grn-/- mouse model, did not detect significant changes in synaptic activity, suggesting that no synapse loss has occurred yet at these early stages of FTD in this model. After the last PET scan, the imaging data were validated via fluorescent immunostaining for pre- and post-synaptic marker proteins SV2 and PSD95, respectively. Quantifications in several brain regions, including the frontal cortex, did not reveal any significant differences in protein expression, supporting the lack of aberrant 18[F]-FDG tracer uptake measured via PET. Additional examinations for activated microglia, a known aspect of FTD pathology recently observed in end Grn-/- mice, did not reveal microglia activation as measured via CD68 immunostaining. These data suggest that Grn-/- mice at 9 and 11 months do not exhibit synaptic dysfunction in the frontal cortex when measured via 18[F]-FDG PET or immunostaining of pre- and postsynaptic marker proteins SV2 and PSD95.
ContributorsWeisman, Hannah (Author) / Sattler, Rita G (Thesis advisor) / Mastroeni, Diego (Committee member) / Velazquez, Ramon (Committee member) / Arizona State University (Publisher)
Created2022
Description
Alzheimer’s Disease (AD) is the most common form of dementia affecting the population over the age of 65. AD is characterized clinically by increasing difficulty with memory and language, resulting in a loss of independence. This is due to the presence of two characteristic protein aggregates in the brain: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Utilizing multiplexed immunofluorescence and dimensional reduction analysis the types of cells present in the hippocampus, the region of the brain most affected by AD, can be explored. Understanding the kinds of cell subtypes present, the mechanism behind how AD develops can be explored. Multiplexed IF was performed on human hippocampus FFPE tissues to detect a total of 37 proteins. Dimensional reduction analysis was performed to identify the four major cell types in the brain: neurons, oligodendrocytes, astrocytes, and microglia. After identifying each cell type, further dimensional reduction analysis was performed within each cell type to identify cell subtypes. A total of 21 neuron, 41 oligodendrocyte, 20 astrocyte, and 22 microglia subtypes were identified. The location of cell subtypes in each region of the hippocampal formation was found to match previous reports, further validating the findings of this project.
ContributorsEllison, Mischa A (Author) / Guo, Jia (Thesis advisor) / Borges, Chad (Committee member) / Mastroeni, Diego (Committee member) / Arizona State University (Publisher)
Created2024
Description
Novel means are needed to diagnose neurodegenerative diseases (NDDs) and cancer, given delays in medical diagnosis and rising rates of disease incidence, prevalence, and mortality worldwide. Development of NDDs and cancer has been linked to environmental toxins. Ensuing epigenetic changes may serve as helpful biomarkers to diagnose amyotrophic lateral sclerosis (ALS), Parkinson’s Disease (PD), and Alzheimer’s Disease (AD) as well as various cancers sooner and more accurately. This dissertation tabulates and evaluates a spectrum of diagnostic matrixes (i.e., soil, sewage sludge, blood) and markers of disease to inform disease surveillance. A literature search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Bradford Hill criteria implicated BMAA, formaldehyde, Mn, Hg, and Zn as environmental factors with strong association to ALS risk. Another PRISMA search identified epigenetic changes (e.g., DNA methylation) in NDD patients associated with environmental toxic exposures to air pollutants, heavy metals, and organic chemicals. Of the 180 environmental toxins hypothesized to be associated with AD, PD, or ALS, four heavy metals (As, Cd, Mn, and Hg) were common to these NDDs. Sources, as well as evidence and proxies of human exposure to these heavy metals and Pb were investigated here, namely the metal industries, and metal concentrations in topsoil, sewage sludge, and blood. Concentrations of Cd and Pb in sewage sludge were found to be significantly correlated with NDD prevalence rates in co-located populations (state-level) with odds ratios of 2.91 and 4.08, respectively. Markers of exposure and disease in urine and feces were also evaluated using PRISMA, finding 73 of 94 epigenetic biomarker panels to be valid for tracking primarily gastric and urinary cancers. In all studies, geospatial analyses indicated a preference in study cohorts located in the U.S., Europe, and the northern hemisphere, leaving underserved many populous regions particularly in the southern hemisphere. This dissertation draws attention to sewage sludge as a currently underutilized proxy matrix for assessing toxic human exposures and further identified a spectrum of particularly attractive, non-invasive biomarkers for future diagnostic use to promote early detection, survivability, and quality of life of individuals at risk of NDDs and cancer.
ContributorsNewell, Melanie Engstrom (Author) / Halden, Rolf U. (Thesis advisor) / Mastroeni, Diego (Committee member) / Lee, Heewook (Committee member) / Arizona State University (Publisher)
Created2023