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Title: Pyroglutamylated amyloid beta peptides enhance non-fibrillogenic aggregation of the unmodified peptide.
Creator: Goldblatt, Gregory, Tatulian, Suren, Chen, Bo, Teter, Kenneth, King, Stephen, University of Central Florida
Abstract / Description: Alzheimer's disease (AD) is accompanied by abnormal extracellular deposition of amyloid b (Ab) peptide. This has led to the amyloid cascade hypothesis, causatively relating Ab with AD. While Ab deposits assume a fibrillar cross-b structure, prefibrillar oligomers of Ab have been identified as the main cytotoxic agents in AD. Pyroglutamylated amyloid beta (AbpE) peptides are N-terminally truncated and pyroglutamylated (at Glu3 or Glu11) Ab molecules that display enhanced cytotoxicity and...
Show moreAlzheimer's disease (AD) is accompanied by abnormal extracellular deposition of amyloid b (Ab) peptide. This has led to the amyloid cascade hypothesis, causatively relating Ab with AD. While Ab deposits assume a fibrillar cross-b structure, prefibrillar oligomers of Ab have been identified as the main cytotoxic agents in AD. Pyroglutamylated amyloid beta (AbpE) peptides are N-terminally truncated and pyroglutamylated (at Glu3 or Glu11) Ab molecules that display enhanced cytotoxicity and represent up to 50% of total Ab in AD brains. AbpE significantly enhances the toxicity of unmodified Ab by an unknown mechanism. Although in situ Ab populations are heterogeneous, the majority of studies have been conducted on single Ab species. Here, we examined the structural and morphological changes that occur in mixed Ab/AbpE samples. Circular dichroism and transmission electron microscopy data indicate that AbpE3-42 forms b-sheet structure and undergoes delayed fibrillogenesis compared to unmodified Ab1-42. Further, AbpE3-42 decelerates b-sheet formation in mixed Ab1-42/AbpE3-42 samples. FTIR measurements, using 13C-labeled Ab1-42 and unlabeled AbpE3-42, indicate that AbpE3-42 inhibits cross-b-sheet formation by Ab1-42, which explains the retardation of fibrillogenesis. FTIR on peptides 13C-labeled at specific segments provided site specific structural information. Based on these data, the monomeric Ab structure has been modeled as a b-hairpin stabilized by intramolecular H-bonding with an N-terminal a-helix. These hairpins likely form higher order aggregates through ionic and hydrophobic interactions between the C-terminus of one hairpin and the N-terminus of another. Utilizing a novel technique, hydration from gas phase, we examined the a-helix to b-sheet transitions of these peptides. When combined, AbpE3-42 and Ab1-42 mutually inhibit intermolecular b-sheet formation, instead promoting formation of AbpE3-42/Ab1-42 hetero-oligomers of intramolecular H-bonding. These hetero-oligomers displayed enhanced toxicity to PC12 cells compared to individual peptides and induced greater calcium release from lipid vesicles than unmodified Ab. These results indicate that Ab and AbpE mutually inhibit fibrillogenesis and stabilize hetero-oligomers of enhanced cytotoxicity, possibly through a membrane permeabilization mechanism. Collectively, our findings lead to a new concept that Ab/AbpE hetero-oligomers, not just Ab or AbpE oligomers, are the main cytotoxic species in AD
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Date Issued: 2016
Identifier: CFE0006108, ucf:51195
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006108

Title: USE OF A MUSIC AND MEMORY PROGRAM BY CAREGIVERS OF PERSONS WITH DEMENTIA.
Creator: Mendez Campos, Barbara, Gammonley, Denise, University of Central Florida
Abstract / Description: Although use of personal music devices by persons with dementia and their caregivers is now widespread, there is limited literature concerning music and memory's effects on caregivers for persons with dementia. Caregivers were provided an iPod by two respite agencies and were encouraged to use it with their care recipient. A mailed survey of 50 caregivers who received an IPod explored: (a) associations between use of an iPod and caregiver self-efficacy, burden, and care recipient functional...
Show moreAlthough use of personal music devices by persons with dementia and their caregivers is now widespread, there is limited literature concerning music and memory's effects on caregivers for persons with dementia. Caregivers were provided an iPod by two respite agencies and were encouraged to use it with their care recipient. A mailed survey of 50 caregivers who received an IPod explored: (a) associations between use of an iPod and caregiver self-efficacy, burden, and care recipient functional abilities, and; (b) if the method of presenting the music playlist was associated with use of the iPod. Associations were examined for 10 complete surveys returned by caregiver respondents using non-parametric methods. There was no relationship between self-efficacy, burden, functional abilities and use of the iPod. A content analysis was conducted of caregiver open-ended responses to questions about factors associated with use of the device. Mean caregiver age in this study was 75 years of age, care recipient mean was 79 years of age. On average caregivers used the IPods 2-3 times per month. Scores on caregiver burden measured by the 12-item Zarit Burden Interview had a mean of 12.5 which suggests a moderate level of burden. Emergent themes from caregiver open-ended responses about using the device revealed care recipients as primary users, use mostly in the evening, and in response to caregiving tasks or difficult care recipient behaviors. Keywords: Music and memory, dementia caregiver burden, self-efficacy
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Date Issued: 2017
Identifier: CFH2000181, ucf:46046
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000181

Title: THE SERVICE LEARNING EXPERIENCE: HOW STORYTELLING EVOLVES IN PEOPLE WITH ALZHEIMER'S AND DEMENTIA AND WHY THIS IS IMPORTANT TO THE CREATIVE WRITING STUDENT AND THE COMMUNITY.
Creator: Spicer, Alice, Thaxton, Terry, University of Central Florida
Abstract / Description: All meaningful communication is a form of storytelling, according to Walter Fisher, who introduced the narrative paradigm to communication theory, and storytelling is universal across cultures and time as the manner in which people comprehend life. Storytelling is also a creative form of art. This interdisciplinary, multimedia work will explore the creative use of non-traditional storytelling to gather information about how creativity evolves in people with Alzheimer's and dementia and why...
Show moreAll meaningful communication is a form of storytelling, according to Walter Fisher, who introduced the narrative paradigm to communication theory, and storytelling is universal across cultures and time as the manner in which people comprehend life. Storytelling is also a creative form of art. This interdisciplinary, multimedia work will explore the creative use of non-traditional storytelling to gather information about how creativity evolves in people with Alzheimer's and dementia and why this is important to both academia and the community. Currently, there is a lot of research available about the debilitating affects of memory loss, but there is very little research available about retained abilities. Perhaps, just as the blind significantly outperform the sighted in tactile experiments, there are some forms of creativity in storytelling in which people with Alzheimer's and dementia may demonstrate more ability than their fully cognizant peers. My goal is to contribute to a small but growing effort to explore "memory loss as more than just memory loss" (Dr. Anne Bastings).
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Date Issued: 2013
Identifier: CFH0004442, ucf:45104
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004442

Title: Pebbles and Shards.
Creator: Kindle, Edith, Bartkevicius, Jocelyn, Uttich, Laurie, Rushin, Patrick, University of Central Florida
Abstract / Description: Pebbles and Shards is a collection of personal essays based on family relationships that focus upon motherhood, responsibility, and the complexity of love and loss. The essays explore how people cope with the inevitability of loss and how they move beyond that loss to find something meaningful, perhaps even beautiful. They reflect upon success and failure in the face of loss and how, either way, life goes on, heedless of people's desires and plans.The essays in Pebbles and Shards, while meant...
Show morePebbles and Shards is a collection of personal essays based on family relationships that focus upon motherhood, responsibility, and the complexity of love and loss. The essays explore how people cope with the inevitability of loss and how they move beyond that loss to find something meaningful, perhaps even beautiful. They reflect upon success and failure in the face of loss and how, either way, life goes on, heedless of people's desires and plans.The essays in Pebbles and Shards, while meant to stand alone, are thematically connected so that, read together, each story resonates with the others. In (")Promises,(") I explore the fear of watching my mother die of Alzheimer's disease. In related essays (")Frame by Frame(") and (")In Darkness,(") I focus on my mother's efforts to struggle with Alzheimer's and how, as an adopted daughter, I underwent a role-reversal and became the mother figure. Other essays, such as (")Heart of a Deadhead(") and (")Circus,(") consider the mothering impulse, especially the guilt and conflict that so often accompany my desire to nurture others. In attempting to support and strengthen those who seem (")weak,(") I have sometimes found that my own actions and thoughts underscore a deeper weakness in myself.As a collection, Pebbles and Shards contemplates the suffering and joy that is a family.
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Date Issued: 2013
Identifier: CFE0004704, ucf:49813
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0004704

Title: TARGETED DELIVERY OF A THERAPEUTIC PROTEIN FOR THE TREATMENT OF ALZHEIMER'S DISEASE.
Creator: Holman, Heather, Sugaya, Kiminobu, University of Central Florida
Abstract / Description: Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are linked to mitochondrial dysfunction and the underexpression of TOM40, a protein with chaperone-like qualities that is responsible for transporting precursor proteins into the mitochondria. Overexpression of TOM40 is reported to partially restore mitochondrial dysfunction and decrease the accumulation of neurotoxic aggregates of ?-synuclein. Our goal is to develop an effective method for delivery of TOM40...
Show moreNeurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are linked to mitochondrial dysfunction and the underexpression of TOM40, a protein with chaperone-like qualities that is responsible for transporting precursor proteins into the mitochondria. Overexpression of TOM40 is reported to partially restore mitochondrial dysfunction and decrease the accumulation of neurotoxic aggregates of ?-synuclein. Our goal is to develop an effective method for delivery of TOM40 protein to the brain. Previous studies have used lentiviruses to carry TOM40 into the hippocampus of ?-synuclein transgenic mice. The disadvantage of lentiviral transfection is the random insertions of the target gene into the host genome, which could cause toxic effects. Synthetic phospholipid vesicles containing TOM40 were considered as an alternative delivery method, but these "liposomes" elicit not only toxicity, but also an immune response. Thus, development of a safer delivery method of TOM40 protein is needed. We investigated exosomes, which are extracellular vesicles originating from multivesicular endosomes filled with protein, lipid, or RNA cargoes for cell-cell communication. Since exosomes are created from host cells, they are non-immunogenic and may be a more desirable method. Expression constructs have been made for the production of TOM40 protein within or on the surface of exosomes. In order to target the delivery of TOM40 to the brain, we attached peptides to the surface of the exosomes, which specifically interact with receptors on neural cells. We attempted to confirm the functionality of the expression constructs through immunocytochemistry followed by flow cytometry and Western blotting.
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Date Issued: 2018
Identifier: CFH2000328, ucf:45803
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000328

Title: STUDIES ON THE NOVEL FUNCTION OF AMYLOID PRECURSOR PROTEIN IN GLIAL DIFFERENTIATION OF NEURAL STEM CELLS.
Creator: Kwak, Young-Don, Sugaya, Kiminobu, University of Central Florida
Abstract / Description: Although amyloid beta (A beta) deposition has been a hallmark of Alzheimer's disease (AD), the physiological function of amyloid precursor protein (APP) is not clear. Our results suggested that high concentration of APP induces glial differentiation while physiological level of APP promotes migration and differentiation of neural stem cell (HNSC). HNSCs were mainly differentiated into astrocytes when they are transplanted into APP transgenic mouse brain or treated with a high...
Show moreAlthough amyloid beta (A beta) deposition has been a hallmark of Alzheimer's disease (AD), the physiological function of amyloid precursor protein (APP) is not clear. Our results suggested that high concentration of APP induces glial differentiation while physiological level of APP promotes migration and differentiation of neural stem cell (HNSC). HNSCs were mainly differentiated into astrocytes when they are transplanted into APP transgenic mouse brain or treated with a high concentration of secreted-type APP (sAPP) in culture. Staurosporine (STS) induced a distinctive astrocytic morphology in NT-2/D1 neural progenitor cells with expressions of APP and astrocyte-specific markers, glial fibrillary acidic protein (GFAP), aspartate transporter, and glutamate transporter-1. Expression of APP is correlated with GFAP expression in both mRNA and protein level in this experiment. Inhibition of APP expression by RNA interference (RNAi) or treatment with MEK1 inhibitor (PD098059), which reduces APP expression by suppressing ERK phosphorylation, abolished GFAP expression. These results indicate that STS induces glial differentiation of neuronal progenitor cells by increasing APP levels through activation of ERK pathway. We also found that APP-induced glial differentiation of neural progenitor NT-2/D1 cells is mediated by activation of IL-6/gp130 and notch signaling pathway. Treatment of APP activated IL-6/gp130 signal pathway via protein-protein interaction between APP and gp130 and it increased the gene expressions of CNTF, gp130 and JAK1, and phosphorylation of STAT3 while gene silencing of CNTF, JAK1 or STAT3 by RNAi, or treatment the cells with antibodies recognizing gp130 suppressed GFAP expression, indicating these molecules are crucial for APP-induced glial differentiation. Thus treatment of sAPP may promote glial differentiation of neural progenitor cells by activation of IL-6/gp130 signaling cascade. Treatment of sAPP increased the generation of notch intracellular domain as well as gene expression of Hes1 but did not change expression levels of notch or its ligands. We also found protein-protein interaction of APP and notch using immunoprecipitation suggesting that glial differentiation of NT-2/D1 cells is mediated by the physical interaction between APP and notch. N-terminal domain of APP (1-205 a.a.) alone can bind to notch and activate these signaling cascade in NT-2/D1 cells. Thus, APP may induce glial differentiation through activation of IL-6/gp130 and notch signal cascade by binding with its N-terminal domain. Taken together, our results suggest that APP regulates neural stem cell (NSC) differentiation through IL-6/gp130 and notch signaling pathway. Furthermore, the activation of both glial differentiation mechanisms may be necessary to potentiate APP-induced glial differentiation of NSC. Altered APP metabolism in Down syndrome and Alzheimer's disease may accelerate premature glial differentiation of NSCs, resulting in gliosis found in these diseases. Although it is not clear that how adult neurogenesis contributes to maintain normal brain function, destruction of neuroreplacement mechanism by NSCs may pose a problem. We may also have to consider effect of APP on the stem cell therapy for these diseases, since HNSCs may not properly differentiate into neurons under these pathological conditions.
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Date Issued: 2006
Identifier: CFE0001375, ucf:46980
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001375

Title: THE ENDOCYTIC PROTEIN NUMB REGULATES APP METABOLISM AND NOTCH SIGNALING: IMPLICATIONS FOR ALZHEIMER'S DISEASE.
Creator: Kyriazis, George, Chan, Sic, University of Central Florida
Abstract / Description: Increased production of amyloid beta (A-beta) peptide, via altered proteolytic cleavage of amyloid protein precursor (APP), and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch1, a membrane receptor that controls cell fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase protein complex in which mutations cause early-onset inherited AD. Numb is...
Show moreIncreased production of amyloid beta (A-beta) peptide, via altered proteolytic cleavage of amyloid protein precursor (APP), and abnormalities in neuronal calcium homeostasis play central roles in the pathogenesis of Alzheimer's disease (AD). Notch1, a membrane receptor that controls cell fate decisions during development of the nervous system, has been linked to AD because it is a substrate for the gamma-secretase protein complex in which mutations cause early-onset inherited AD. Numb is an evolutionarily conserved endocytic adapter involved in the internalization of transmembrane receptors. Mammals produce four Numb isoforms that differ in two functional domains, a phosphotyrosine-binding domain (PTB) and a proline-rich region (PRR). Recent studies showed that the PTB domain of Numb interacts with the cytoplasmic tails of APP and Notch but the functional relevance of these interactions with respect to AD pathogenesis is not clear. In the current studies, we proposed to investigate the biological consequences of the interaction of the Numb proteins with APP and Notch in neural cells stably overexpressing each of the four human Numb proteins. In the first part of our studies, we found that expression of the Numb isoforms lacking the insert in the PTB (SPTB-Numb) caused the abnormal accumulation of cellular APP in the early endosomes, and increased the levels of C-terminal APP fragments and A-beta. By contrast, expression of the Numb isoforms with the insert in PTB (LPTB-Numb) leads to the depletion of cellular APP and coincides with significantly lower production of APP derivatives and A-beta. The contrasting effects of the Numb isoforms on APP metabolism were not attributed to differences in the expression of APP nor the activities of the various APP-processing secretases. In the second part of our studies, we found that expression of SPTB-Numb protein enhances neuronal vulnerability to serum deprivation-induced cell death by a mechanism involving the dysregulation of cellular calcium homeostasis. Neural cells expressing SPTB-Numb exhibited enhanced Notch activity, which markedly upregulated the expression of transient receptor potential canonical 6 (TRPC6) channels enhancing calcium entry in response to store depletion. We also found that serum deprivation increased TRPC6 expression, mediating the serum deprivation-induced death in neural cells. Interestingly, expression of LPTB-Numb protein suppressed serum deprivation-induced activation of Notch and the subsequent upregulation of TRPC6 and cell death. Finally, we showed that the Numb proteins differentially impact Notch activation by altering the endocytic trafficking and processing of Notch. Taken together, these studies demonstrate that aberrant expression of the Numb proteins may influence APP metabolism and Notch-mediated cellular responses to injury by altering their endocytic trafficking and processing.
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Date Issued: 2008
Identifier: CFE0002233, ucf:47917
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0002233

Title: VOICE ONSET TIME PRODUCTION IN INDIVIDUALS WTH ALZHEIMER'S DISEASE.
Creator: Baker, Julie Baker, Ryalls, Jack, University of Central Florida
Abstract / Description: In the present study, voice onset time (VOT) measurements were compared between a group of individuals with moderate Alzheimer's disease (AD) and a group of healthy age- and gender-matched peers. Participants read a list of consonant-vowel-consonant (CVC) words, which included the six stop consonants. Recordings were gathered and digitized. The VOT measurements were made from oscillographic displays obtained from the Brown Laboratory Interactive Speech System (BLISS) implemented on an IBM...
Show moreIn the present study, voice onset time (VOT) measurements were compared between a group of individuals with moderate Alzheimer's disease (AD) and a group of healthy age- and gender-matched peers. Participants read a list of consonant-vowel-consonant (CVC) words, which included the six stop consonants. Recordings were gathered and digitized. The VOT measurements were made from oscillographic displays obtained from the Brown Laboratory Interactive Speech System (BLISS) implemented on an IBM-compatible computer. VOT measures for the participants' six stop consonant productions were subjected to statistical analysis. The results of the study indicated that differences in VOT values were not statistically significant in the speakers with Alzheimer's disease from the normal control speakers.
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Date Issued: 2006
Identifier: CFE0001269, ucf:46918
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0001269

Title: STRUCTURAL TRANSITION DURING FIBRILLOGENESIS OF AMYLOID ? PEPTIDE.
Creator: Sidrak, George, Tatulian, Suren, University of Central Florida
Abstract / Description: Alzheimer's Disease (AD) is a neurodegenerative disease marked by progressive neuronal cell death, leading to dementia. AD is the most common disease that results in dementia and largely affects the elderly, with five million people in the United States diagnosed with the disease as of 2015 and approximately 35 million people worldwide. Diseases resulting in dementia cost the US healthcare system an estimated $172 billion in 2010 and that cost is expected to increase as the population ages...
Show moreAlzheimer's Disease (AD) is a neurodegenerative disease marked by progressive neuronal cell death, leading to dementia. AD is the most common disease that results in dementia and largely affects the elderly, with five million people in the United States diagnosed with the disease as of 2015 and approximately 35 million people worldwide. Diseases resulting in dementia cost the US healthcare system an estimated $172 billion in 2010 and that cost is expected to increase as the population ages and as diagnostic techniques improve so that more people are treated (Holtzman, 2011). The disease was first reported by psychiatrist Alois Alzheimer at the onset of the 20th century, when one of his patients "suffered memory loss, disorientation, hallucinations and delusions and died at the age of 55," then was found to have severe brain atrophy post-mortem (Cipriani, Dolciotti, Picchi, & Bonuccelli, 2011). There are palliative treatments available that marginally slow disease progression but there is currently no cure for the disease (Awasthi, Singh, Pandey, & Dwivedi, 2016). More research is needed to develop effective therapeutic strategies to combat the disease. Currently, AD cytotoxicity is believed to be caused by increased amyloid ? (A?) peptide plaque deposition in the brain, as described by the amyloid cascade hypothesis (Barage & Sonawane, 2015). The current understanding is that oligomers of A? peptide lead to neuronal death through multiple mechanisms, most notably hyper-phosphorylation of the tau protein. Having a better understanding of the structural changes in the fibrillization process of A? will provide a broader insight into mechanisms of cell death and open new possibilities for pharmacological treatments, which is what this research intends to provide.
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Date Issued: 2017
Identifier: CFH2000178, ucf:45994
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH2000178

Title: YOUNG ONSET DEMENTIA: THE CHILD'S EXPERIENCE WITH COPING.
Creator: Zeher, Jamie, Loerzel, Victoria, University of Central Florida
Abstract / Description: Young onset dementia (YOD) affects not only the person diagnosed, but the family unit as a whole. It is estimated that as many as 500,000 people in the United States have YOD and around 250,000 children are involved in caring for these people. A child of a parent with YOD can begin to experience negative effects when the child begins to take part in caregiving for the person with young onset dementia (PWYOD). Feelings of stress, anger, fear of the future, depression, social isolation, and...
Show moreYoung onset dementia (YOD) affects not only the person diagnosed, but the family unit as a whole. It is estimated that as many as 500,000 people in the United States have YOD and around 250,000 children are involved in caring for these people. A child of a parent with YOD can begin to experience negative effects when the child begins to take part in caregiving for the person with young onset dementia (PWYOD). Feelings of stress, anger, fear of the future, depression, social isolation, and increasing responsibility of caring for the PWYOD can be felt by children as caregivers. Research shows that children of people with YOD have reported an extreme lack of support and decreased communication within the family. The purpose of this thesis was to examine current interventions designed to improve coping for children of parents with YOD. A review of literature using CINAHL, Medline, and PsychINFO was conducted to gather peer-reviewed articles and journals relating to interventions to help children of parents with YOD cope. However, no studies have discussed interventions specifically for the child. Therefore, information was pulled from 5 studies regarding what children of people with YOD feel has helped them, in their respective experiences, to deal with the stresses of a parent with YOD. Research suggests that individualized care should be provided for these children based on: age, developmental stage, and experience. Children have reported that they cope by spending time away from the home, participating in extracurricular activities, and spending time with friends. Clear communication by all members of the family is also reported to be vital in easing the stresses of caring for a parent with YOD. While children have developed these coping mechanisms, interventions need to be formally designed and their effect on improving coping examined. Analyzing the experiences of the children with parents with YOD is necessary for clinicians to gain insight into what interventions worked for this population, and what interventions need to be created for further and more individualized support.
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Date Issued: 2013
Identifier: CFH0004405, ucf:45147
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004405

Title: Cerium oxide nanoparticles act as a unique catalyst and scavenge nitric oxide and peroxynitrite and decrease RNS in vitro and in vivo.
Creator: Dowding, Janet, Self, William, Bossy-Wetzel, Ella, Zervos, Antonis, Seal, Sudipta, Santra, Swadeshmukul, University of Central Florida
Abstract / Description: Cerium oxide nanoparticles (CeO2 NPs)(nanoceria) have been shown to possess a substantial oxygen storage capacity via the interchangeable surface reduction and oxidation of cerium atoms, cycling between the Ce4+ and Ce3+ redox states. Reduction of Ce4+ to Ce3+ causes oxygen vacancies or defects on the surface of the crystalline lattice structure of the particles, generating a cage for redox reactions to occur. The study of the chemical and biological properties of CeO2 NPs has expanded...
Show moreCerium oxide nanoparticles (CeO2 NPs)(nanoceria) have been shown to possess a substantial oxygen storage capacity via the interchangeable surface reduction and oxidation of cerium atoms, cycling between the Ce4+ and Ce3+ redox states. Reduction of Ce4+ to Ce3+ causes oxygen vacancies or defects on the surface of the crystalline lattice structure of the particles, generating a cage for redox reactions to occur. The study of the chemical and biological properties of CeO2 NPs has expanded recently, and the methods used to synthesize these materials are also quite diverse. This has led to a plethora of studies describing various preparations of CeO2 NPs for potential use in both industry and for biomedical research. Our own work has centered on studies that measure the ability of water-based CeO2 NPs materials to reduce reactive oxygen and nitrogen species in biological systems, and correlating changes in surface chemistry and charge to the catalytic nature of the particles. The application in experimental and biomedical research of CeO2 NPs began with the discovery that water-based cerium oxide nanoparticles could act as superoxide dismutase mimetics followed by their ability to reduce hydrogen dioxide similar to catalase. While their ROS scavenging ability was well established, their ability to interact with specific RNS species, specifically nitric oxide (NO) or peroxynitrite (ONOO-) was not known. The studies described in this dissertation focus on the study of RNS and cerium oxide nanoparticles.Our in vitro work revealed that CeO2 NPs that have higher levels of reduced cerium sites (3+) at the surface (which are effective SOD mimetics) are also capable of accelerating the decay of peroxynitrite in vitro. In contrast, CeO2 NPs that have fewer reduced cerium sites at the particle surface (which also exhibit better catalase mimetic activity) have NO scavenging capabilities as well as some reactivity with peroxynitrite. Our studies and many others have shown cerium oxide nanoparticles can reduce ROS and RNS in cell culture or animal models. The accumulation of ROS and RNS is a common feature of many diseases including Alzheimer's disease (AD). Testing our CeO2 NPS in cortical neurons, we used addition of A? peptide as an AD model system. CeO2 NPs delayed A?-induced mitochondrial fragmentation and neuronal cell death. When mitochondrial ROS levels are increased, mitochondrial fission is activated by DRP1 S616 phosphorylation. Specifically, our studies showed the reduction of phosphorylated DRP1 S616 in the presence of CeO2 NPs. Results from our studies have begun to unravel the molecule mechanism behind the catalytic nature of how CeO2 NPs reduce ROS/RNS in biological systems and represents an important step forward to test the potential neuroprotective effects of CeO2 NPs in model systems of AD.A plethora of studies describing various preparations of CeO2 NPs for potential use in both industry and for biomedical research have been described in the past five years. It has become apparent that the outcomes of CeO2 NPs exposure can vary as much as the synthesis methods and cell types tested. In an effort to understand the disparity in reports describing the toxicity or protective effects of exposure to CeO2 NPs, we compared CeO2 NPs synthesized by three different methods; H2O2 (CNP1), NH4OH (CNP2) or hexamethylenetetramine (HMT-CNP1). Exposure to HMT-CNP1 led to reduced metabolic activity (MTT) at a 10-fold lower concentration than CNP1 or CNP2 and surprisingly, exposure to HMT-CNP1 led to substantial decreases in the ATP levels. Mechanistic studies revealed that HMT-CNP1 and CNP2 exhibited robust ATPase (phosphatase) activity, whereas CNP1 lacked ATPase activity. HMT-CNP1 were taken up into HUVECs far more efficiently than the other preparations of CeO2 NPs. Taken together, these results suggest the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the mechanism of the toxicity of this preparation of CeO2 NPs, and may suggest ATPase activity should be considered when synthesizing CeO2 NPs for use in biomedical applications. Overall the studies have uncovered two new catalytic activities for water-based CeO2 NPs (NO scavenging and accelerated decay of peroxynitrite), demonstrated their ability to reduce RNS in an AD cell culture model as well as identifying a catalytic activity (phosphatase) that may underlie the observed toxicity of CeO2 NPs reported in other studies.
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Date Issued: 2012
Identifier: CFE0004782, ucf:49783
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0004782

Title: In Vitro Characterization of Unmodified and Pyroglutamylated Alzheimer's Amyloid beta peptide.
Creator: Matos, Jason, Tatulian, Suren, Teter, Kenneth, Davidson, Victor, University of Central Florida
Abstract / Description: Plaques of amyloid ? peptide (A?) are a hallmark trait of Alzheimer's disease (AD). However, the precise role of A? aggregates is not well understood. Recent studies have identified that naturally occurring N-terminal truncation and pyroglutamylation of A? significantly increases its neurotoxicity by an unknown mechanism. Content of pyroglutamylated A? (pE-A?) in AD brains has been shown to reach up to 50% of total A?. Modified pE-A? co-aggregates with A? by a seeding mechanism and forms...
Show morePlaques of amyloid ? peptide (A?) are a hallmark trait of Alzheimer's disease (AD). However, the precise role of A? aggregates is not well understood. Recent studies have identified that naturally occurring N-terminal truncation and pyroglutamylation of A? significantly increases its neurotoxicity by an unknown mechanism. Content of pyroglutamylated A? (pE-A?) in AD brains has been shown to reach up to 50% of total A?. Modified pE-A? co-aggregates with A? by a seeding mechanism and forms structurally distinct and highly toxic oligomers. We studied structural transitions of the full-length A?1-42, its pyroglutamylated form A?pE3-42, their 9:1 (A?1-42/A?pE3-42) and 1:1 molar combinations. Transmission electron microscopy was used to directly visualize the fibrils of the samples in a buffer mimicking physiological environment. Atomic force microscopy measurements were done to determine rate of second nucleation events in fibrils. Thioflavin-T fluorescence indicated that low ionic strength suppressed the aggregation of A?pE3-42 but promoted that of A?1-42, suggesting different paths of fibrillogenesis of unmodified A? and pE-A?. Interestingly, A?pE3-42 at only 10% significantly facilitated the fibrillization of A?1-42 at near physiological ionic strength but had little effect at low salt. Circular dichroism and Fourier transform infrared (FTIR) spectroscopy were used to characterize the structural transitions during fibrillogenesis. In aqueous buffer, both unmodified A? and pE-A? peptides adopted parallel intermolecular ?-structure. Interestingly, A?pE3-42 contained lower ?-sheet content than 13C-A?1-42, while retaining significantly larger fractions of ?-helical and turn structures. Structural details of A? and pE-A? combinations were unveiled by isotope-edited FTIR spectroscopy, using 13C-labeled A?1-42 and unlabeled A?pE3-42. When exposed to environmental humidity, A?pE3-42 not only maintained an increased fraction of ?-helix but also was able to reverse 13C-A?1-42 ?-sheet structure. These data provide a novel structural mechanism for pE-A? hypertoxicity; pE-A? undergoes fasternucleation due to its increased hydrophobicity, thus promoting formation of smaller, hypertoxic oligomers of partial ?-helical structure.
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Date Issued: 2014
Identifier: CFE0005378, ucf:50465
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0005378

Title: AMYLOID-BETA42 TOXICITY REDUCTION IN HUMAN NEUROBLASTOMA CELLS USING CHOLERA TOXIN B SUBUNIT-MYELIN BASIC PROTEIN EXPRESSED IN CHLOROPLASTS.
Creator: Ayache, Alexandra, Daniell, Henry, University of Central Florida
Abstract / Description: Alzheimer's disease (AD) is an age progressive neurodegenerative brain disorder, affecting 37 million people worldwide. Cleavage of amyloid precursor protein by β- and γ-secretase produces the amyloid-beta (Aβ) protein, which significantly contributes to AD pathogenesis. The Aβ aggregates, formed at the surface of neurons and intracellularly, cause neurotoxicity and decrease synaptic function. Inhibiting or degrading Aβ accumulation is a key goal for development of new AD treatments. Evidence...
Show moreAlzheimer's disease (AD) is an age progressive neurodegenerative brain disorder, affecting 37 million people worldwide. Cleavage of amyloid precursor protein by β- and γ-secretase produces the amyloid-beta (Aβ) protein, which significantly contributes to AD pathogenesis. The Aβ aggregates, formed at the surface of neurons and intracellularly, cause neurotoxicity and decrease synaptic function. Inhibiting or degrading Aβ accumulation is a key goal for development of new AD treatments. Evidence shows that human Myelin Basic Protein (MBP) binds to and degrades Aβ thereby, preventing cytotoxicity. A potential method for oral drug delivery that will allow plant-derived bioencapsulated MBP to pass through intestinal epithelium and bypass denaturing stomach acidity is quite novel. Cholera Toxin B subunit (CTB), when fused with MBP, can serve as a vehicle for oral delivery of this chloroplast expressed therapeutic protein into the systemic circulation. Within chloroplast, CTB forms a pentameric structure that binds to GM1 ganglioside receptors, allowing receptor-mediated endocytosis. In order to investigate protein entry through neuronal GM1 receptors, we first created CTB fused to the green fluorescent protein (GFP). Incubation of this fusion protein with human neuroblastoma cells resulted in GFP entry into these cells whereas GFP alone was unable to enter. Similarly, co-incubation of CTB-MBP, via neuronal GM1 binding, allowed MBP to reduce neurotoxicity of Aβ42 treated cells by 37.1%. Delivery of CTB-MBP through GM1 receptor mediated binding should therefore facilitate oral administration, storage, heat stability and low cost AD treatment.
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Date Issued: 2012
Identifier: CFH0004249, ucf:44916
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFH0004249

Title: HYBRID ADULT NEURON CULTURE SYSTEMS FOR USE IN PHARMACOLOGICAL TESTING.
Creator: Edwards, Darin, Hickman, James, University of Central Florida
Abstract / Description: Neuronal culture systems have many applications, such as basic research into neuronal structure, function, and connectivity as well as research into diseases, conditions, and injuries affecting the brain and its components. In vitro dissociated neuronal systems have typically been derived from embryonic brain tissue, most commonly from the hippocampus of E18 rats. This practice has been motivated by difficulties in supporting regeneration, functional recovery and long-term survival of adult...
Show moreNeuronal culture systems have many applications, such as basic research into neuronal structure, function, and connectivity as well as research into diseases, conditions, and injuries affecting the brain and its components. In vitro dissociated neuronal systems have typically been derived from embryonic brain tissue, most commonly from the hippocampus of E18 rats. This practice has been motivated by difficulties in supporting regeneration, functional recovery and long-term survival of adult neurons in vitro. The overall focus of this dissertation research was to develop a dissociated neuronal culture system from human and animal adult brain tissue, one more functionally and developmentally correlative to the mature brain. To that end, this work was divided into five interrelated topics: development of an adult in vitro neuronal culture system comprised of electrically functional, mitotically stable, developmentally mature neurons from the hippocampus of adult rats; creation of stable two-cell neuronal networks for the study of synaptic communication in vitro; coupling of electrically active adult neurons to microelectrode arrays for high-throughput data collection and analysis; identification of inadequacies in embryonic neuronal culture systems and proving that adult neuronal culture systems were not deficient in similar areas; augmentation of the rat hippocampal culture system to allow for the culture and maintenance of electrically active human neurons for months in vitro. The overall hypothesis for this dissertation project was that tissue engineered in vitro systems comprised of neurons dissociated from mature adult brain tissue could be developed using microfabrication, defined medium formulations, optimized culture and maintenance parameters, and cell-cycle control. Mature differentiated glutamatergic neurons were extracted from hippocampal brain tissue and processed to purify neurons and remove tissue debris. Terminally differentiated rat hippocampal neurons recovered in vitro and displayed mature neuronal morphology. Extracellular glutamate in the culture medium promoted neuronal recovery of electrical function and activity. After recovery, essential growth factors in the culture medium caused adult neurons to reenter the cell cycle and divide multiple times. Only after reaching confluence did some neurons stop dividing. Strategies for inhibition of neuronal mitotic division were investigated, and manipulation of the cdk5 pathway was ultimately found to prevent division in vitro. Prevention of mitotic division as well as optimization of culture and maintenance parameters resulted in a neuronal culture system derived from adult rats in which the neuronal morphology, cytoskeleton and surface protein expression patterns, and electrical activity closely mirrored mature, terminally differentiated adult neurons in vivo. Improvements were also made to the growth surfaces on which neurons attached, regenerated, and survived long-term. Culture surfaces, in this case glass cover slips, were modified with the chemical substrate N-1 [3-(trimethoxysilyl) propyl]-diethylenetriamine (DETA) to create a covalently modified interface with exposed cell-adhesive triamine groups. DETA chemical surfaces were also further modified to create high-resolution patterns, useful in creating engineered two-cell networks of adult hippocampal neurons. Adult hippocampal neurons were also coupled to microelectrode array systems (MEAs) and recovered functionally, fired spontaneously, and reacted to synaptic antagonists in a manner consistent to adult neurons in vivo. Last, neurons from the brains of deceased Alzheimer's disease (AD) patients and from brain tissue excised during surgery for Parkinson's disease (PD), Essential Tremor (ET), and brain tumor were isolated and cultured, with these neurons morphological regenerating and electrically recovering in vitro.
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Date Issued: 2011
Identifier: CFE0004045, ucf:49127
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0004045

Title: Neurological profile of older ApoE-PON1 double knockout mice.
Creator: Mitra, Connie, Parthasarathy, Sampath, Kim, Yoon-Seong, Zhao, Jihe, University of Central Florida
Abstract / Description: Atherosclerosis is a cardiovascular disease where plaques made up of lipids in the form of cholesterol ester build up in the carotid and innominate arteries that supply blood to the brain. Accumulation of the plaques limit the flow of blood and nutrients to the brain, leading to diminished oxygen supply, increased oxidative stress and cell death. All these have been implicated in Alzheimer's disease (AD). Alzheimer's disease, a chronic, progressive, age related neurodegenerative disorder is...
Show moreAtherosclerosis is a cardiovascular disease where plaques made up of lipids in the form of cholesterol ester build up in the carotid and innominate arteries that supply blood to the brain. Accumulation of the plaques limit the flow of blood and nutrients to the brain, leading to diminished oxygen supply, increased oxidative stress and cell death. All these have been implicated in Alzheimer's disease (AD). Alzheimer's disease, a chronic, progressive, age related neurodegenerative disorder is the most common form of dementia in the elderly accounting for 60-80% of the cases. Clinically, Alzheimer's disease is characterized by loss of memory, damage of brain tissues, and neuronal and synaptic loss. Pathologically, it is delineated by accumulation of amyloid beta and tau proteins forming senile plaques and neurofibrillary tangles respectively. Apolipoprotein E (ApoE) polymorphism, increased oxidative stress and products of lipid peroxidation are associated with atherosclerosis and Alzheimer's disease. ApoE is a glycosylated protein that mediates plasma lipoprotein metabolism. ApoE isoforms have differential effect on amyloid beta aggregation and clearance, thus playing an important role in Alzheimer's pathology. Serum paraoxonase 1 (PON1) is a lipoprotein associated antioxidant enzyme that prevents lipid peroxidation. S100B protein is a plasma biomarker, altered expression of which has been implied in AD. We propose the hypothesis that combined deficiencies in apolipoprotein E and antioxidant defense (established by the lack of PON1), together with dyslipidemia and development of carotid atherosclerosis in aging mice would reflect Alzheimer's pathology. The brains of young and old ApoE-PON1 double knockout (DKO) mice and control C57BL/6J mice were harvested. Atherosclerotic lesions were quantified by Image J. RNA was isolated, cDNA was synthesized and quantitative RT-PCR was performed to detect mRNA levels of S100B. Blood levels of S100B protein was measured by ELISA. Brain tissues were stained with Hematoxylin and Eosin stain and 4G8 immunostain to detect histopathological changes. The blood brain barrier (BBB) is altered in AD resulting in increased permeability and vascular dysfunction. The vascular permeability of BBB was analyzed by Evans Blue Dye (EBD) assay. The results showed that the older DKO mice had severe carotid atherosclerosis, increased levels of serum S100B protein and elevated mRNA levels of S100B. Histological examination showed the presence of characteristic hallmarks of AD. The leakage of EBD into brain parenchyma indicated disruption of BBB. The results suggest that diminished blood flow and nutrient supply to the brain due to atherosclerosis and increased oxidative stress might contribute to Alzheimer's pathology. We suggest that older ApoE-PON1 DKO mice may serve as a model of Alzheimer's disease and prevention of atherosclerosis might promote regression of Alzheimer's disease.
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Date Issued: 2016
Identifier: CFE0006483, ucf:51407
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006483

Title: Development of human and rodent based in vitro systems toward better translation of bench to bedside in vivo results.
Creator: Berry, Bonnie, Hickman, James, Khaled, Annette, Lambert, Stephen, Sugaya, Kiminobu, University of Central Florida
Abstract / Description: Prospective medicinal compounds progress through multiple testing phases before becoming licensed drugs. Testing of novel compounds includes a preclinical phase where the potential therapeutic is tested in vitro and/or in animal models in vivo to predict its potential efficacy and/or toxicity in humans. The failure of preclinical models to accurately predict human drug responses can lead to potentially dangerous compounds being administered to humans, or potentially beneficial compounds being...
Show moreProspective medicinal compounds progress through multiple testing phases before becoming licensed drugs. Testing of novel compounds includes a preclinical phase where the potential therapeutic is tested in vitro and/or in animal models in vivo to predict its potential efficacy and/or toxicity in humans. The failure of preclinical models to accurately predict human drug responses can lead to potentially dangerous compounds being administered to humans, or potentially beneficial compounds being kept in development abeyance. Moreover, inappropriate choice in model organism for studying disease states may result in pushing forward inappropriate drug targets and/or compounds and wasting valuable time and resources in producing much-needed medications. In this dissertation, models for basic science research and drug testing are investigated with the intention of improving current preclinical models in order to drive drugs to market faster and more efficiently. We found that embryonic rat hippocampal neurons, commonly used to study neurodegenerative disease mechanisms in vitro, take 3-4 weeks to achieve similar, critical ion-channel expression profiles as seen in adult rat hippocampal cultures. We also characterized a newly-available commercial cell line of human induced pluripotent stem cell-derived neurons for their applicability in long-term studies, and used them to develop a more pathologically relevant model of early Alzheimer's Disease in vitro. Finally, we attempted to create an engineered, layered neural network of human neurons to study drug responses and synaptic mechanisms. Utilization of the results and methods described herein will help push forward the development of better model systems for translation of laboratory research to successful clinical human drug trials.
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Date Issued: 2015
Identifier: CFE0006261, ucf:51031
Format: Document (PDF)
PURL: http://purl.flvc.org/ucf/fd/CFE0006261

Alzheimer's (6)	+ -
Alzheimer's Disease (4)	+ -
Alzheimer's disease (4)	+ -
amyloid beta (4)	+ -
dementia (2)	+ -

fibrillogenesis (2)	+ -
microelectrode array (2)	+ -
APP (1)	+ -
Alzheimer's disease (AD) (1)	+ -
Amyloid beta (1)	+ -
Amyloid beta plaques (1)	+ -
Amyloid fibrillization (1)	+ -
Amyloid precursor protein (1)	+ -
Amyloid-Beta (1)	+ -
Atherosclerosis (1)	+ -
Blood Brain barrier (1)	+ -
Caregivers (1)	+ -
Cerium oxide nanoparticles (1)	+ -
Child Abuse (1)	+ -
Chloroplast (1)	+ -
Cholera Toxin B Subunit (1)	+ -
Dementia (1)	+ -
Essay (1)	+ -
Evans Blue Dye (1)	+ -
Exosome (1)	+ -
Exosomes (1)	+ -
Family (1)	+ -
Fourier transform infrared spectroscopy (1)	+ -
Ganglioside M1 (1)	+ -
Glial differentiation (1)	+ -

ETD Collection (10)	+ -
Honors Collection (6)	+ -

University of Central Florida (16)	+ -
Sugaya, Kiminobu (3)	+ -
Tatulian, Suren (3)	+ -
Hickman, James (2)	+ -
Teter, Kenneth (2)	+ -

Ayache, Alexandra (1)	+ -
Baker, Julie Baker (1)	+ -
Bartkevicius, Jocelyn (1)	+ -
Berry, Bonnie (1)	+ -
Bossy-Wetzel, Ella (1)	+ -
Chan, Sic (1)	+ -
Chen, Bo (1)	+ -
Daniell, Henry (1)	+ -
Davidson, Victor (1)	+ -
Dowding, Janet (1)	+ -
Edwards, Darin (1)	+ -
Gammonley, Denise (1)	+ -
Goldblatt, Gregory (1)	+ -
Holman, Heather (1)	+ -
Khaled, Annette (1)	+ -
Kim, Yoon-Seong (1)	+ -
Kindle, Edith (1)	+ -
King, Stephen (1)	+ -
Kwak, Young-Don (1)	+ -
Kyriazis, George (1)	+ -
Lambert, Stephen (1)	+ -
Loerzel, Victoria (1)	+ -
Matos, Jason (1)	+ -
Mendez Campos, Barbara (1)	+ -
Mitra, Connie (1)	+ -

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