Browsing by Subject "Alzheimer’s Disease"
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Item Alzheimer's Fibroblasts are More Susceptible to Oxidative Stress(2001-05-01) Marshall, Pamela L.; Neeraj Agarwal; Robert GracyMarshall, Pamela L., Alzheimer’s Fibroblasts Are More Susceptible to Oxidative Stress. Master’s of Science (Biomedical Sciences). May 2001. Recent evidence indicates that oxidative stress contributes to neuronal death in Alzheimer’s disease (AD). In addition, it has been suggested that AD is a systemic illness in which the development of the disease is only visible in the brain. The aim of this research is to develop experimental procedures using a simple cell model, the fibroblast, to determine if proteins derived from AD skin fibroblasts are more sensitive to oxidation by reactive oxygen species than non-AD cells, and to assess the ability of antioxidants to prevent this oxidative damage in AD fibroblasts. Preliminary findings suggest that changes in sensitivity are already detectable in fibroblasts from AD patients, probably as a consequence of genetic component as well as other risk factors. Therefore, this biochemical marker might have the potential for identifying individuals at risk for AD.Item Cellular and Molecular Mechanisms that Distinguish the Effects of Progestorone and Medroxyprogesterone Acetate on Neuroprotection(2006-07-28) Kaur, Paramjit; Goldfarb, Ronald; Singh, Meharvan; Agarwal, NeerajKaur, Paramjit. Cellular and Molecular Mechanisms That Distinguish the Effects of Progesterone and Medroxyprogesterone Acetate on Neuroprotection., Doctor of Philosophy, (Pharmacology and Neuroscience), July, 2006, 203 pp., 5 illustrations, 20 figures and bibliography. Women have a higher prevalence for Alzheimer’s disease (AD) than men, suggesting that the precipitous decline in gonadal hormone levels following the menopause may contribute to the risk of developing AD. However, principal results from the Women’s Health Initiative concluded that women taking conjugated equine estrogens combined with medroxyprogesterone acetate (MPA, tradename: Prempro) incurred more harmful than beneficial outcomes versus the placebo group (Rossouw et al., 2002). This dissertation was aimed at determining if the discrepancy between basic science reports and these clinical studies could have been due to the synthetic progestin, MPA. I hypothesized that P4 and MPA differed in their ability to protect against the excitotoxic/oxidative insult, glutamate. Further, I proposed that this difference in neuroprotective potential would be reflected in the difference in the ability of these hormones to elicit key effectors of two neuroprotection-associated signaling pathways, the ERK/MAPK and P13-Kinase pathways. Finally, studies were initiated to evaluate the potential importance of BDNF (brain-derived neurotrophic factor) in mediating the protective effects of P4. I used organotypic explants of the cerebral cortex, and found that both P4 and MPA elicit the phosphorylation of ERK and Akt, two signaling pathways implicated in neuroprotection, with maximal phosphorylation occurring at a concentration of 100 nM. Interestingly, P4 protected against glutamate- induced toxicity however, while an equimolar concentration of MPA (100nM) did not. Further, P4 resulted in an increase in BDNF, while MPA did not. Our data bring into question the relevance of using MPA as a component of hormone therapies in postmenopausal women, and instead, argue that the relevant progestin for use in treating brain-related disorders is progesterone. Collectively, the data presented here suggest that P4 is protective via multiple, and potentially related mechanism, and importantly, its neurobiology is different from the clinically used progestin, MPA.Item Genetic Modulation of β-Amyloid Neurotoxicity and Protection by Nicotinic Agents(2007-05-01) Martin, Shelley E.; Basu, Alakananda; Forster, Michael; Singh, MeharvanMartin, Shelley E., Genetic Modulation of β-Amyloid Neurotoxicity and Protection by Nicotinic Agents. Master of Science (Pharmacology and Neuroscience), May, 2007, 53 pp., 7 figures, 2 tables, bibliography, 95 titles. Β-amyloid1-42 (Aβ42) has been implicated in the pathogenesis of Alzheimer’s disease (AD); however, the amount of this peptide in the brain does not correlate well with the presence or severity of AD. This project tested the hypothesis that individual differences exist in susceptibility to Aβ42 neurotoxicity arising from the differences in the expression of α7 nicotinic acetylcholine receptors α7 nACHRs). This hypothesis was tested in primary neuronal cultures derived from inbred mouse strains which differ in expression of α7 nAChRs. Also, the ability of nicotinic agents to modulate Aβ42 toxicity was examined. Significant strain differences in susceptibility to Aβ42 toxicity were found; however, these were not related to levels of α7 nAChRs. Additionally, strain differences were found in the ability of α7-selective partial agonist, an α7-selective antagonist and a α4β2 nAChR-selective antagonist to protect against this toxicity. Inbred strains of mice may be useful in uncovering the pathophysiology of AD.Item Identification of Oxidized Proteins in Alzheimer's Disease(2002-08-01) Choi, Joungil; Gracy, Robert R.; Harris, B.; Lacko, Andras G.Joungil Choi, Identification of Oxidized Proteins in Alzheimer’s Disease. Doctor of Philosophy (Molecular Biology and Immunology). August, 2002. Pages-110. Tables 8. Figures 24. Oxidative modification of specific proteins is central to the pathology of Alzheimer’s disease (AD). The purpose of this study was to identify the oxidation-sensitive proteins in neuronal cells, fibroblasts from AD subjects, and in the blood of AD patients. In all cases, age-matched non-Alzheimer’s samples were used as controls. Proteomic methods were used to isolate and characterize the oxidized proteins. These included two-dimensional gel electrophoresis, immunolocalization of oxidized proteins and identification by MALDI-TOF mass spectroscopic methods. It was hypothesized that knowledge of these critical oxidation-sensitive proteins would shed light on the underlying mechanism of the disease. In addition, it was postulated that these proteins might prove to be biomarkers for early detection and monitoring the progress of the disease. The results show that two different oxidative stressors (H2O2 generated enzymatically, or the amyloid beta peptide, AB25-35) induce apoptotic cell death and oxidation of specific proteins (heat shock protein 60 and vimentin) in skin fibroblasts from AD subjects and in neuronal cells. In addition, the results indicate that susceptibility of these two proteins to oxidative stress is increased in fibroblasts from AD patients, compared to non-AD controls. Pretreatment with antioxidants (e.g., vitamin E or flavonoids) protect these proteins from oxidative damage. Both heat shock protein 60 and vimentin, have been suggested to function as antiapoptotic proteins. Thus, their oxidative damage could lead to the apoptotic neuronal cell death in Alzheimer’s disease. In the blood plasma of AD subjects, isoforms of fibrinogen gamma chain and alpha-1 antitrypsin were found to be oxidized. These proteins exhibited to a two- to six-fold greater specific oxidation index in plasma from AD subjects when compared to controls. Both of these proteins have been suggested to be implicated in oxidation-mediated damage of inflammation in the AD brain.Item Oxidative Stress Alters IP3 Receptor Function in the Neuronal Cell Line HT22(2008-05-01) Longoria, Sandra; Peter Koulen; Kati Prokai; Tina MachuSandra Longoria., Oxidative Stress Alters IP3 Receptor Function in the Neuronal Cell Line HT22, Master of Science (Biomedical Sciences), May 2008, 72 pp., 25 Figures. Oxidative stress contributes to the genesis of several neurodegenerative disorders such as Alzheimer’s Disease (AD). Oxidants such as, tert-butyl hydrogen peroxide (tBHP), have been used in in vitro models of neurodegeneration to induce oxidative stress. Small changes in the regulation of the intracellular calcium (Ca2+) concentration can contribute to brain aging and increase vulnerability of neurons to cellular and functional damage in neurodegenerative diseases. In neurons, inositol 1, 4, 5-trisphosphate (IP3) is a second messenger that is generated through receptor activity at the plasma membrane. IP3 receptors (IP3R) are located on endoplasmic reticulum (ER) membranes and are intracellular calcium channels (ICC) that release Ca2+ into the cytoplasm in response to activation by their ligand IP3. The goal of the present study was to measure the contribution of ICCs to Ca2+ dysregulation in neurons experiencing oxidative stress. I tested the hypothesis that oxidative stress induced with tBHP causes increased intracellular Ca2+ release via activation of IP3 receptors. I used the murine hippocampal cell line HT22, as a model for neuronal oxidative stress. Immunocytochemistry and Ca2+ imaging experiments were performed to identify areas of altered IP3R expression and activity under normal conditions and induced oxidative stress. tBHP treatment increased expression and Ca2+ release activity of neuronal IP3 receptors. My findings support that oxidative stress as seen in a number of neurodegenerative diseases negatively affects regulation of Ca2+ release through increased expression and activity of IP3 receptors.Item Regulation of intracellular calcium channels by their associated proteins homer 1 and presenilin 1(2006-05-01) Hwang, Sung-Yong; Koulen, Peter; Dillon, Glenn; Singh, MeharvanSung-Yong, Hwang, Regulation of intracellular calcium channels by their associated proteins homer 1 and presenilin 1. Doctor of Philosophy (Pharmacology and Neuroscience), May, 2006, 184 pp., 4 tables, 20 illustrations, 74 titles. In neurons, Calcium (CA2+) serves as a critical intracellular messenger that regulates a variety of cellular processes such as gene expression, neurotransmitter release, cell death, and synaptic plasticity. Therefore, it is essential for neurons to control their Ca2+ levels tightly. Ca2+ is released within the cell from intracellular stores such as the endoplasmic reticulum by activation of intracellular Ca2+ channels (ICCs) such as the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs). Each of these two groups of ICC has three isoforms. A number of associated proteins of these two ICCs that were shown to modulate activity of the respective channel have been identified. Homer 1, a synaptic scaffolding protein not only physically associated with IP3R type1 (IP3R1), but also changes the activity of IP3R1, suggesting that Homer 1 is involved in intracellular Ca2+ signaling. Based on the similarity in amino acid sequence and molecular and physiological properties among IP3R isoforms and the fact that IP3R type 3 (IP3R3) contains the proline-rich motif (PPxxFr) that is required for the interaction with Homer, it was hypothesized that Homer 1 associates with IP3R3, leading to changes in the channel activity. Presenilin 1 (PS1) is a transmembrane protein, being expressed in cell body, dendrites, and axon in the neuron. Mutations in PS1 account for most cases of early-onset familial Alzheimer’s disease (AD). PS1 was shown to associate with RyRs and to modulate their channel activity. Therefore, it was hypothesized that specific regions of PS-1 bind to RyR type 2 (RyR2), a major isoform in the brain, resulting in changes in the channel activity. Homer 1c was shown to associate with IP3R3, leading to a decrease in channel activity. A specific region of PS1 that interacts with RyR2 was identified to increase the channel activity of RyR2. Results of the present study contributed to the understanding of the nature of intracellular Ca2+ signaling as well as the mechanisms of action by which ICCs are regulated by their associated proteins. These findings provide the rationale for novel strategies to study neurological disorders including AD and epilepsy that are mediated by Ca2+ dysregulation.Item TARRANT COUNTY RESOURCES FOR PATIENTS WITH ALZHEIMER’S DISEASE(2014-03) Septien, Spencer J.; David, Jonathan; Kjolhede, Lauren; Sims, MeaganThe purpose of this investigation was to identify comprehensive community resources available in the Tarrant County area for people diagnosed with Alzheimer’s disease (AD). AD is a debilitating illness that requires lifelong care and support. There is currently no cure for AD making community resources an invaluable asset to any person afflicted with the disease. Our goal was to educate the community on the basics of AD and to identify local resources which could help patients and their families cope with the effects and burdens of AD. Our group conducted research using http://www.tarrantcounty211.org/ to locate organizations within Tarrant County that offer a variety of comprehensive resources for individuals with AD. We analyzed the services provided by the Alzheimer’s Association- North Texas Chapter, Memories in the Making, James L. West Alzheimer’s Center, and the Texas Alzheimer’s Research and Care Consortium. The Alzheimer’s Association- North Texas Chapter should be the primary resource for local residents afflicted with AD. The organization offers support, education, and programs such as TrialMatch and professional training. TrialMatch is a free program designed to locate clinical trials for people suffering from AD using one’s unique diagnosis and symptoms. Professional training for medical personnel helps educate caretakers on the proper way to care for this unique subset of the population. Memories in the Making is an organization that offers a therapeutic outlet for AD patients by allowing individuals to express themselves through art and exercises that stimulate creativity. The James L. West Alzheimer’s Center is a comprehensive care center offering activities, education, and specialized care for any stage of the disease. The Texas Alzheimer’s Research and Care Consortium is a large statewide research project that strives to better understand the disease by examining the potential role of genetic factors and phenotypic characteristics of subjects in the epidemiology and pathology of AD. Tarrant County has a variety of services available to patients and families coping with Alzheimer’s disease and its effects. These services are aimed at education, support, and research with the ultimate goal of decreasing the morbidity and mortality of those individuals suffering with Alzheimer’s disease.Item THE ROLE OF OXIDATIVE STRESS, INFLAMMATION, AND METABOLIC FACTORS IN ALZHEIMER’S DISEASE RISK AMONG NON-HISPANIC WHITE AND MEXICAN AMERICAN MALES(2014-03) Septien, Spencer J.; Barber, Robert C.; Cunningham, RebeccaResearch suggests that the biological marker profile associated with Alzheimer's disease (AD) differs between non-Hispanic whites and Mexican Americans. High levels of oxidative stress are thought to precede the development of classical AD pathology including that of neurofibrillary tangles and senile plaques. Assuming a relationship between levels of oxidative stress and the pathogenesis of AD, we chose to analyze the serum biological markers of male Mexican American and non-Hispanic white AD patients under conditions of high or low oxidative stress. We stratified the sample based on the level of oxidative stress, using a cut point of 12 μM serum homocysteine. Special consideration was given to markers associated with inflammation and metabolic disease, which have been shown to impact AD pathophysiology. Baseline levels of testosterone and glutathione s transferase (GST) were also measured for each demographic. Inflammatory involvement was apparent in both Mexican American men and non-Hispanic white males, with a much more profound affect among non-Hispanic whites. Metabolic factor involvement did not appear to be as significant among non-Hispanic white males in contrast to a clear involvement in Mexican American men. Levels of oxidative stress did not appear to alter the inflammatory or metabolic profile relationship in either demographic. Baseline levels of testosterone and GST were higher in Mexican Americans. Analysis suggests that ethnicity and oxidative stress impact AD pathophysiology and associated serum markers. Purpose (a): Research suggests that the biological marker profile associated with Alzheimer's disease (AD) differs between non-Hispanic whites and Mexican Americans. High levels of oxidative stress are thought to precede the development of classical AD pathology including that of neurofibrillary tangles and senile plaques. Methods (b): Assuming a relationship between levels of oxidative stress and the pathogenesis of AD, we chose to analyze the serum biological markers of male Mexican American and non-Hispanic white AD patients under conditions of high or low oxidative stress. We stratified the sample based on the level of oxidative stress, using a cut point of 12 μM serum homocysteine. Special consideration was given to markers associated with inflammation and metabolic disease, which have been shown to impact AD pathophysiology. Baseline levels of testosterone and glutathione s transferase (GST) were also measured for each demographic. Results (c): Inflammatory involvement was apparent in both Mexican American men and non-Hispanic white males, with a much more profound affect among non-Hispanic whites. Metabolic factor involvement did not appear to be as significant among non-Hispanic white males in contrast to a clear involvement in Mexican American men. Levels of oxidative stress did not appear to alter the inflammatory or metabolic profile relationship in either demographic. Baseline levels of testosterone and GST were higher in Mexican Americans. Conclusions (d): Analysis suggests that ethnicity and oxidative stress impact AD pathophysiology and associated serum markers.