Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item Metabolic Profiling of Brain Microvascular Endothelial Cells: Investigating the Role of Sex, Stress, APOE Genotype, and Exercise in Alzheimer's Disease Risk(2024) Weber, Callie; Clyne, Alisa M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Alzheimer’s disease (AD) is the 7th leading cause of death in the United States, yet there are still no effective treatments to prevent or slow the progression of the disease. AD develops from a combination of genetic and lifestyle risk factors including female sex, elevated stress hormone exposure, the apolipoprotein (APOE) ε4 genotype, and a sedentary lifestyle. In order to better identify the manifestations of AD, it is vital to understand how each of these risk factors impact brain health and lead to neurological dysfunction associated with AD. Brain microvascular endothelial cells (BMEC) line the blood vessels of the brain and have specialized tight junctions designed to strictly regulate nutrient and waste transfer between the blood and the brain. Two of the early indicators of AD development are breakdown of the tight junctions and whole brain glucose hypometabolism. Since BMEC form the first line of defense for the brain against neurotoxic compounds in the blood and are responsible for glucose transport to the rest of the brain, the overarching goal of this thesis is to understand how female sex, elevates stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle induce breakdown of tight junction proteins and glucose hypometabolism in BMEC. I first demonstrate that female sex exacerbates endothelial dysfunction in response to high levels of a stress hormone, Angiotensin II (AngII). Specifically, I show that in response to AngII, female endothelial cells increase oxidative stress and inflammatory responses while male endothelial cells do not. Next, I used CRISPR/Cas9 to generate a set of induced pluripotent stem cells (iPSC) homozygous for the APOE ε3 and ε4 genotype and differentiated them into BMEC (hiBMEC). Using the hiBMEC I showed the APOE ε4 genotype induces barrier deficiencies that are partially mediated through reduced levels of protein deacetylase Sirtuin 1 (SIRT1), and that the APOE ε4 genotype causes glucose hypometabolism through decreased insulin signaling. Finally, by adding serum from sedentary and exercise trained individuals to genotype-matched hiBMEC, I show that APOE ε3 and ε4 hiBMEC have divergent responses to treatment with serum from sedentary and exercise trained individuals. Treatment with exercise trained serum increases SIRT1 and glycolytic enzymes compared to sedentary serum, while exercise trained serum decreases SIRT1 and glycolytic enzymes in APOE ε4 hiBMEC compared to sedentary serum. The work described in this thesis gives a fundamental, mechanistic understanding to the roles of female sex, stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle in BMEC dysfunction and hypometabolism, giving insight into how these factors contribute to AD development and progression.Item DEVELOPMENT OF AN ACCELERATED ALZHEIMER’S DISEASE IN VITRO MODEL WITH THE ADDITION OF PROGERIN(2023) Xue, Huijing; Cao, Kan; Cell Biology & Molecular Genetics; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Alzheimer’s Disease (AD) is one of the most common causes of dementia. Twopathological features of AD include amyloid plaques and neurofibrillary tangles. The mechanism underlying the disease's onset and progression remains unclear. Lamin A is an essential component of the nuclear lamina, and nuclear lamina plays a vital role in essential cell functions. Specific mutations in lamin A yield a truncated protein called progerin that causes Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease. Despite the low expression of lamin A in the brain, several studies reported abnormal lamin A accumulation in patients' hippocampus through the different stages of AD. Besides, there are a lot of common phenotypes between AD and HGPS. Meanwhile, one of the challenges of studying AD is the model issue. It is difficult to recapitulate all AD pathology in a single model, and most models are time-consuming. This dissertation focuses on goals: (1) exploring the potential role of lamin A in AD and (2) facilitating the AD model development. To investigate the potential role of lamin A in AD, I overexpressed either lamin A or progerin in neural cells and checked the phenotypes in Chapter II. Early cell death is closely associated with neuronal loss in AD. After ectopically expressing lamin A in neural cells, early cell death was slightly increased. Progerin could worsen these phenotypes. Oxidative stress and cell cycle re-entry are early events in neurodegeneration and are associated with increased cell death. With the ectopic expression of lamin A, neural cells exhibited slightly elevated oxidative stress and significantly increased cell cycle reactivation. Both two events were significantly increased with exogenous progerin. These results provide insights into how lamin A is involved in neurodegeneration. Besides, progerin addition could further disrupt cellular homeostasis and therefore provide a potential environment for modeling late-onset disease. Most of the current cellular models for AD require several months to display AD phenotypic features, mainly because of the lack of an aging environment in the in vitro cell culture, which is an essential player in age-related neurodegeneration. To provide the aging environment for modeling AD, I examined the impacts of exogenous progerin expression on the neural progenitor cells carrying familial AD mutations (FAD) in Chapter III. Exogenous progerin could accelerate hallmark AD phenotype exhibition from 8-16 weeks to 3-4 weeks, including increased tau phosphorylation and Aβ42/Aβ40 ratio in 2D cell culture, and accumulation of amyloid plaques in 3D cell culture. Additional AD cellular phenotypes, including elevated cell death and cell cycle re-entry, were significantly increased after progerin intervention as well. Together, these results indicated that the approach with progerin expression could create an accelerated model for modeling AD development and future drug screening.Item EFFICACY OF ESTROGEN TREATMENT IN A MURINE MODEL OF ALZHEIMER'S DISEASE(2012) Schlappal, Anna Elise; Ottinger, Mary Ann; Neuroscience and Cognitive Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Clinically, Alzheimer's Disease (AD) presents with cognitive dysfunction, cell death, and amyloid-beta (AB) plaque and neurofibrillary tangle (NFT) formation. Moreover, age and gender are primary risk factors; women are at much higher risk for developing AD compared to men. Estrogens may be neuroprotective; however, clinical use in hormone replacement therapy (HRT) is controversial due to potential adverse effects. Experiments were conducted using the APPswe/PS1dE9 (DTG) and APPswe/PS1M146V/TauP301L (3xTgAD) transgenic mouse models to assess the efficacy of an estrogen pro-drug, estradiol-quinol (E2Q). Treatment groups consisted of vehicle, estradiol (E2), or E2Q in intact and ovariectomized (OVX) DTG females, intact DTG males, and intact 3xTgAD females and males. The objectives of this study were to 1) characterize AD progression in a double transgenic (DTG) murine model and compare the efficacy of treatment with estradiol (E2) or E2Q in ovariectomized (OVX) and intact females, 2) compare the effects of E2Q in males, 3) determine if E2Q affects neurodegenerative disease progression in the triple transgenic (3xTgAD) murine model in both males and females, and 4) assess the effects of the neurodegenerative disease progression on mitochondrial function and determine if E2Q affects these endpoints. E2Q did not stimulate uterine tissue and proved to be an effective intervention; treated DTG mice had better cognitive behavior, decreased amyloid precursor protein (APP), and amyloid beta (AB) protein levels. Taken together, these data suggest that E2Q has potential as a therapeutic for AD patients.Item The Relationship Between Exercise and Cognitive Function: Is It Altered by APOE Genotype?(2006-12-11) Conery, Ryan; Hatfield, Brad D; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The risk of minor cognitive decline and dementia increases with advancing age. Thus, as the average lifespan of humans continues to rise the number of people that are affected by dementia will rapidly increase. Dementia is described as multiple cognitive deficits that adversely impact activities of daily living. Lifestyle behaviors may prove critical in delaying or preventing the onset of cognitive decline and dementia. Specifically, exercise has been shown to decrease reaction time, improve executive function, and maintain performance on gross measures of cognitive ability in an aging population. Further, physical activity becomes even more important when the genetic susceptibility for dementia rises. Apolipoprotein (APOE) e4 is one such risk factor and is associated with the development of Alzheimer's disease (AD). Severe memory loss is one defining symptom of AD and greatly reduces quality of life for afflicted individuals. The purpose of this investigation is to determine the specific behavioral impact of physical activity on those who are genetically at risk for AD compared to those who are not. Sixty cognitively normal individuals between 50 - 70 years old were assessed on medical history, gross cognitive function, physical activity, memory performance (Sternberg memory task), executive control function (Eriksen flanker task), and finally APOE genotype. Using hierarchical regression techniques, memory and executive function scores were regressed on age, education, genotype, physical activity, and the interaction between genotype and physical activity. Analysis revealed that on the more difficult conditions of the memory task as physical activity level increased, reaction time significantly decreased for APOE e4 carriers. No such relationship existed for noncarriers. These results imply, compared with other cognitive challenges, physical activity serves a protective role for maintaining memory, particularly in those who are at a genetic risk for developing dementia.