Browsing by Subject "Alzheimer's disease"
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Item A phenomenological approach to understanding the changes in marital intimacy for caregivers married to a spouse with Alzheimer's Disease(Texas Tech University, 2005-05) Adams, Mark S.; Harris, Steven M.; Tacon, Anna M.; Stelle, Charlie D.; Wampler, Karen S.Alzheimer’s disease or a related dementia (ADRD) can create enormous strain and burden for family caregivers. But the potential for relationship disruption via changes in intimacy seem to be the greatest for couples in long-term marriages. I conducted intensive interviews with spouses who provide care for their partner with ADRD. I wanted to better understand how some spousal caregivers had managed to maintain a sense of continuity in their marital intimacy, and to understand what may have kept others from maintaining that same closeness. I also explored the role of physical intimacy and/or sexuality in facilitating the process of marital continuity. I proceeded from the assumption that people want to feel close to those they love and that a person can be active in creating that closeness. I believe that the sexual relationship holds a great potential for maintaining feelings of closeness and connection. I used a phenomenological approach to describe, analyze, and interpret data of spouses' lived experiences. Then I attempted to extrapolate those experiences into clinical interventions or suggestions to assist clinicians who may work with similar couples. My analysis shows that spouses who provide care for their partner with ADRD moved through a process of change that affected their opportunities for further intimacy. The disease processes eventually led to a diagnosis of ADRD for the impaired spouse. A sense of uncertainty or ambiguity grew as the symptoms of the disease increased. Caregiving spouses were faced with the challenge of emotionally and psychologically separating the symptoms of ADRD from the personhood of their partner. The growing ambiguity was usually accompanied by challenges (both emotional and practical) to cope and adjust to the new dynamics. Adjustment and working through the challenges did not automatically mean that the spouse who was providing care would feel emotionally close to his or her partner, although it was much more likely. There is one last overarching influence that affects the whole process – marital history. This study has implications for clinical theory and interventions for practitioners working with couples or spouses who provide care to a partner with ADRD.Item A phenomenological approach to understanding the changes in marital intimacy for caregivers married to a spouse with Alzheimer's Disease(2005-05) Adams, Mark S.; Harris, Steven M.; Tacon, Anna M.; Stelle, Charlie D.; Wampler, Karen S.Alzheimer's disease or a related dementia (ADRD) can create enormous strain and burden for family caregivers. But the potential for relationship disruption via changes in intimacy seem to be the greatest for couples in long-term marriages. I conducted intensive interviews with spouses who provide care for their partner with ADRD. I wanted to better understand how some spousal caregivers had managed to maintain a sense of continuity in their marital intimacy, and to understand what may have kept others from maintaining that same closeness. I also explored the role of physical intimacy and/or sexuality in facilitating the process of marital continuity. I proceeded from the assumption that people want to feel close to those they love and that a person can be active in creating that closeness. I believe that the sexual relationship holds a great potential for maintaining feelings of closeness and connection. I used a phenomenological approach to describe, analyze, and interpret data of spouses' lived experiences. Then I attempted to extrapolate those experiences into clinical interventions or suggestions to assist clinicians who may work with similar couples. My analysis shows that spouses who provide care for their partner with ADRD moved through a process of change that affected their opportunities for further intimacy. The disease processes eventually led to a diagnosis of ADRD for the impaired spouse. A sense of uncertainty or ambiguity grew as the symptoms of the disease increased. Caregiving spouses were faced with the challenge of emotionally and psychologically separating the symptoms of ADRD from the personhood of their partner. The growing ambiguity was usually accompanied by challenges (both emotional and practical) to cope and adjust to the new dynamics. Adjustment and working through the challenges did not automatically mean that the spouse who was providing care would feel emotionally close to his or her partner, although it was much more likely. There is one last overarching influence that affects the whole process – marital history. This study has implications for clinical theory and interventions for practitioners working with couples or spouses who provide care to a partner with ADRD.Item Adaptive responses of central cholinergic systems in transgenic mice(2006-08) Hartmann, Joachim; Klein, Jochen; Lockridge, Oksana; Löffelholz, Konrad; Mehvar, Reza; Stoll, JamesIn the current thesis, the function of the septohippocampal cholinergic nervous system was investigated in transgenic mouse models pertinent to Alzheimer’s disease. First, a transgenic model of increased amyloid formation and deposition was investigated to see whether a cholinergic deficit, as observed in the human disease, is present in those animals. These mice express both a mutated human amyloid precursor protein and human presenilin-1 and generate amyloid peptide and neuritic plaques in an age-dependent manner. High-affinity choline uptake (HACU) into corticohippocampal synaptosomes showed no difference between double mutant transgenic mice and controls, indicating unchanged turnover of the neurotransmitter, acetylcholine (ACh). Extracellular levels of ACh, measured in the dorsal hippocampus using microdialysis, were not significantly different between groups. The response of these levels to stimulation with either scopolamine or by exposure of animals to a novel environment was also unchanged between mutant mice and controls, indicating retained capability of the central cholinergic system to respond to different challenges. In conclusion, this study demonstrated that amyloid pathology can occur without compromising hippocampal cholinergic neurotransmission. For the second part of this thesis, mice deficient for the enzyme acetylcholinesterase (AChE) were obtained; they serve as a model of the predominant treatment used in Alzheimer’s disease, inhibition of AChE. Microdialysis in dorsal hippocampus revealed vastly elevated baseline levels of ACh, whereas baseline levels of Ch were reduced. Selective inhibition of butyrylcholinesterase (BChE) further increased these levels of ACh in AChE-deficient, but not in control mice. This observation, for the first time, provides clear evidence that BChE can hydrolyze ACh in the brain of a living organism. Elevated levels of ACh were sensitive to the absence of calcium and to tetrodotoxin, confirming their neuronal origin. A compensatory increase in HACU was found, indicating increased transmitter turnover. Furthermore, it was demonstrated that extracellular levels of Ch become rate-limiting for ACh release in the absence of AChE. Finally, a relative failure of presynaptic negative autofeedback receptors was observed. The conclusion is reached that, in the absence of AChE, ACh hydrolysis is maintained to a considerable degree by BChE. Moreover, compensatory changes in the absence of AChE include upregulation of HACU and functional loss of inhibitory autofeedback receptors. In summary, both mouse models demonstrate that central cholinergic systems can respond to a wide range of challenges with a remarkable degree of adaptation.Item Aging Americans and a Changing Mind: Alzheimer vs. Law Enforcement(Law Enforcement Management Institute of Texas (LEMIT), 2017) Wesselski, FredAmerican senior citizens are the fastest-growing population in the United States. (Bureau of Labor Statistics, 2015). With the increase of the senior citizen populace, there are challenges not only facing the aging populace but also American law enforcement agencies. The challenges will come from the increase of Alzheimer’s disease and the increase in calls for service to law enforcement to assist the patients with Alzheimer’s disease. The major obstacles in dealing with this disease are twofold. The first obstacle is the increase of new patients with Alzheimer’s, which is estimated to be 500,000 new cases each year (“Sources for Alzheimer’s Disease”, 2017). The second obstacle is the lack of training and experience of law enforcement officers having to understand and deal with Alzheimer’s patients. Law enforcement agencies should be preparing for this disease by providing the proper training. The Texas Commission on Law Enforcement (TCOLE) and elected officials at the state level should be working together to mandate training regarding Alzheimer’s disease and mental health for law enforcement officers. The local elected official and Alzheimer’s caregivers must coordinate with the local law enforcement agency to help identify the patients and make known the needs of the patient. Without proper training and information, the Alzheimer’s patient and officers are at risk of harm or death.Item Alzheimer's disease: effects of perceived genetic risk on offspring(Texas Tech University, 1997-12) Chapa, Beatrice MarieAlzheimer's Disease (AD) has been called a family disease due to the increased involvement of family members in the care of Alzheimer's patients as the disease progresses. A substantial amount of research also suggests an increased genetic risk for the development of AD in first-degree relatives. Unfortunately, while ample research is available examining the genetic risk of AD, the effects this information has on the offspring of AD patients has not been explored. In current practice, it appears that family members often obtain information about their Increased risk for developing AD, but no supportive or comprehensive educational information is provided to help them cope with this information. This study explored concerns regarding perceived genetic risk for AD in adults with and without a family history of dementia. Variables which might contribute to concerns regarding perceived genetic risk were also examined, including level of depression and anxiety, amount of contact and quality of relationship with the family member with dementia, knowledge regarding AD, social support, financial stress, age, gender, severity of memory impairment in the family member, and family history of memory problems. This study was the first to find that family members of AD patients perceive themselves to be at significantly higher risk for developing AD, and that the spouses of these family members are concerned about the possibility of becoming a caregiver. Spousal support and financial stability were found to moderate the level of concern regarding one's perceived genetic risk for developing AD. These results suggest there may be a need for more accurate information on the genetic risk factors for AD.Item Alzheimer's patient caregivers: experimental drug treatment participation as a moderator of caregiver outcomes(Texas Tech University, 1995-05) Banken, Cheryl HallCaring for a family member with Alzheimer's disease has been associated with a variety of negative outcomes. Hence, it is important to gain an understanding of the factors that contribute to these outcomes as an avenue toward identifying interventions that may have moderating effects. There is a growing body of evidence that psychological resources and social support can mitigate the impact of caregiving stressors. Psychological resources may include appraisals, coping skills and expectancies, while social support may range fi^om formal services to informal family networks. The purpose of the present study was to investigate how involvement in an experimental drug treatment affected expectancies and/or appraisals about caregiving and the care receiver's condition. Antecedent variables that have been inconsistently linked with negative caregiver outcomes were also examined. This study had two phases of assessment, with 166 caregivers participating at Time 1 and 109 caregivers six weeks later at Time 2. There were four treatment conditions reflecting two different drug conditions, a screening failure condition and a group uninvolved in research. Within each treatment group, both primary and non-primary caregivers were assessed for burden, depression, hopelessness, anger, desire to institutionalize (DTI), locus of control, positive outcomes and optimistic expectancies.Item Art making practices for groups of individuals with Alzheimer's disease(2016-05) Coonrod, Ellen Claire-Murray; Adejumo, Christopher O., 1959-; Bolin, Paul EThrough the method of action research, this study reflects upon the individual practice of an art educator in facilitating visual art making experiences for a group of adults with dementia caused by Alzheimer’s disease. The study’s qualitative data consists of interviews with class facilitators, photos of the class environment and resulting artwork, and written observations, which were analyzed for emergent themes supporting the participants’ cognitive and social engagement. In adopting Kitwood and Bredin’s (1992) approach of person-centered care, the study connected their twelve indicators of relative well-being to observations of engagement in the class. The discovered themes include personal objects and stories, collaboration, mood, repetition, stimulating materials, multiple steps, individualized assistance, minimized distractions, and limited options. These described attributes could provide a resource for those designing and facilitating similar experiences for adults with Alzheimer’s disease.Item Automated identification of references to head trauma in medical records(Texas Tech University, 1989-12) Djajaputra, IsakNot availableItem Designing Alzheimer’s special care facilities that includes consideration for the Islamic culture(Texas Tech University, 2008-05) Obeidat, Asem M.; Shroyer, Jo Ann L.; Amor, Cherif; Harp, Shelley S.Previous writings about Muslim minorities in the United States included various aspects of cultural diversity such as historical development, immigration, and political influences. However, there is a lack of research studies considering the correlation between the built environment and the Muslim users. Particularly, previous studies have not included the physical environment considered for Muslims or the Islamic culture in the United States. This exploratory study aimed to identify environmental design elements that can accommodate the Islamic culture in the United States Alzheimer’s special care facilities for the Muslim elderly population diagnosed with Alzheimer’s disease. The study investigated cultural aspects of American Muslims to be employed when designing environments for American Muslims diagnosed with Alzheimer’s disease. A focus group and a questionnaire were used to accomplish the purpose of the study. A focus group study was conducted in the Islamic Center of the South Plains, Lubbock, Texas. Nine participants (American Muslims) were interviewed in the focus group study. A content analysis procedure was used to analyze the gathered data of the focus group. A questionnaire was developed based on the outcomes of the focus group and distributed to four Islamic communities in the state of Texas including Dallas, Huston, San Antonio, and Lubbock. The questionnaire was completed by 649 American Muslims. The data collected was analyzed using descriptive statistics procedure (frequency distributions) from the Statistical Package for the Social Sciences (SPSS). The results of data analysis were used to generate design recommendations to be employed when designing Alzheimer’s special care facilities for Muslims diagnosed with Alzheimer’s disease.Item Experimental and computation study of protein interactions with lipid nanodomains(2013-05) Qiu, Liming; Cheng, Kelvin K.; Vaughn, Mark W.; Sanati, Mahdi; Khare, Rajesh; Quitevis, Edward L.Protein lipid interactions are significantly relevant to understanding of a wide variety of biological phenomena in general. In particular, human beta-amyloid protein is closely related to the pathogenesis of Alzheimer's disease. Due to its high propensity to self-aggregate, beta-amyloid protein is difficult to study with experiments. Molecular dynamics simulations is capable of providing atomistic details of the protein lipid interactions; therefore, is an important theoretical tool to investigate these subtle interactions and offer insights to the pathogenesis of Alzheimer's disease. In this dissertation, I studies the protein lipid interactions with several systems with different lipid composition and protein conformations. I developed computational tools to quantitatively analyze lipid perturbations due to protein interactions, since it is commonly believed that the neurotoxicity of beta-amyloid protein is through perturbation of the lipid membrane. I discovered that for the case of a beta-amyloid dimer on the surface of lipid bilayers, the perturbation effect of protein is correlated to the degree of disorder of the protein in term of its secondary structure. Meanwhile, for a system where a beta-amyloid protein was partially inserted into the bilayer, the protein insertion rate was regulated by both the secondary structure of the protein and the lipid environment. Especially, a scaling relation between the insertion rate and degree of disorder was found. Even though molecular dynamics simulations is a powerful tool in studying atomistic protein lipid interactions, it is not efficient in sampling the free energy landscape of the system; hence results are biased by the initial structure of the system. I developed a multiscale molecular simulation scheme to increase the efficiency in free energy landscape sampling by switching the system between different spatial resolutions, i.e., atomistic and coarse-grain representations of the system. Using this method, I discovered a novel protein lipid orientation, which has implications in understanding the biochemical pathway of the protein as well as developing therapeutic interventions. Finally, I also developed a Monte Carlo method to estimate molecule volumes accurate to atomistic scale. This method is directly applicable to lipid membrane system with heterogeneous components including proteins; it is a useful tool for not only investigating protein lipid interactions but also calibration of force field parameters for classical molecular dynamics simulations.Item Factor Structure of the Geriatric Depression Scale and its Relationship to Cognition in Alzheimer's Disease(2012-04-19) Havins, Whitney; Massman, Paul J.; Hiscock, Merrill; Dulay, Jr., Mario F.Evidence suggests that patients with Alzheimer’s disease (AD) experience more frequent and severe apathy and depression than their healthy age counterparts. Moreover, some studies have shown that apathy and depression are associated with greater cognitive and functional decline in these patients. Previous research has shown the Geriatric Depression Scale to be capable of identifying symptoms of both apathy and dysphoria in older adults. However, no study to date has systematically explored whether the Geriatric Depression Scale measures symptoms of apathy and dysphoria in patients with AD and related these constructs to performance on neuropsychological measures. This study employed exploratory factor analysis to identify factors of the Geriatric Depression Scale in a sample of 569 patients with pure probable AD. A four-factor solution was obtained, yielding factors associated with apathy, dysphoria, social withdrawal, and cognitive impairment. It was hypothesized that symptoms of apathy would be associated with cognitive and functional impairment, even after controlling for dysphoria. Two-way ANOVAs showed that endorsement of Apathy factor items was associated with greater impairment in verbal memory and motor speed, as well as functional impairment. Dysphoria was not associated with any cognitive or functional variables. Findings suggest that the GDS may be used as a screening measure for symptoms of apathy in AD, hopefully aiding early identification and intervention to reduce patient and caregiver burden.Item Herpes simplex-1 as an additive risk factor for cognitive decline in apolipoprotein E4 carriers(2015-08) Eagan, Danielle Erin; Haley, Andreana P.; Schnyer, David M; Maddox, Todd; Mumford, Jeanette; Sullivan, ChristopherThe identification of early, modifiable risk factors for cognitive decline presents the most promising opportunity for intervention. To date one of the most robustly replicated risk factors for the most common form of dementia, Alzheimer’s disease (AD), is the Apolipoprotein E4 (ApoE4) allele. Risk for sporadic and familial late onset AD increases nearly threefold for each E4 allele an individual carries. However some E4 carriers do not develop cognitive decline, and many non-E4 carriers do, highlighting the role of environmental variables in the progression to clinical symptoms. There is evidence that herpes simplex-1 (HSV-1), a common neurotropic viral infection with affinity for the same brain structures affected in AD, is an acquired risk factor that may compound the genetic risk associated with ApoE4. We examined the interaction between the ApoE4 allele and HSV-1 in cognitively normal middle-aged adults using neuropsychological testing and structural and functional neuroimaging. Neuropsychological assessments were used to determine cognitive differences between groups. Structural neuroimaging was used to measure group differences in bilateral hippocampal volumes, and cortical thickness in brain regions most likely to be affected by AD and HSV-1. Functional neuroimaging was used to examine differences in resting- state brain activity within the default mode network (DMN), a network known for alterations in functional connectivity during the progression from normal aging to AD. With regard to cognition we found that ApoE4 carriers performed significantly lower on tests of executive functioning when they were infected with HSV-1. HSV-1 infection alone also correlated with significantly lower full scale IQ (FSIQ). Within the structural domain we found that individuals with ApoE4 had significantly smaller bilateral hippocampal volumes compared to individuals without the virus, regardless of HSV-1 status. Within the functional domain we failed to find any group differences in functional connectivity within the DMN. Together these findings suggest that HSV-1 may contribute to cognitive changes linked to cognitive vulnerability, and that ApoE4 may contribute to structural brain vulnerability. Because these factors are identifiable prior to the onset of frank cognitive decline, antiviral intervention could be considered as a means of mitigating risk for cognitive decline.Item Identifying the behavioral and psychological symptoms of dementia in stages of Alzheimer’s disease: A meta-analysis(2012-08) Williams, Ben; Harter, Stephanie; Cohen, Lee M.; Cukrowicz, Kelly C.; Mumma, GregoryDementia of the Alzheimer’s Type (DAT) is an insidious disease that, over time, affects all aspects of neurocognitive functioning, eventually resulting in death. While neurocognitive symptoms of DAT certainly impair overall functioning and well-being, the behavioral and psychological symptoms (BPSD) of DAT have traditionally been overshadowed by the more overt neurocognitive symptoms of DAT. Numerous correlates and risk factors have been identified for individual BPSD. Some studies have even examined the presence of sub-groups, clusters, or syndromes of BPSD. The current study examined, using meta-analytic techniques, the occurrence of BPSD in different levels of DAT severity (mild, moderate, and severe). It was hypothesized total BPSD would increase from mild to moderate DAT, while decreasing in the severe stage. It was also believed individual BPSD would be more prevalent in certain DAT severity levels. While there was only one significant difference among the different DAT severity levels, many of the effect sizes were in the expected directions. Limitations in the empirical literature include lack of data available for BPSD in different severity levels of DAT and studies that do not differentiate the DAT severity levels in the participants.Item Measuring Dementia of the Alzheimer Type More Precisely(2012-11-29) Lowe, Deborah AnneAlzheimer?s disease (AD) progressively impairs cognitive and functional abilities. Research on pharmacological treatment of AD is shifting to earlier forms of the disease, including preclinical stages. However, assessment methods traditionally used in clinical research may be inappropriate for these populations. The Alzheimer Disease Assessment Scale-cognitive (ADAS-cog), a commonly used cognitive battery in AD research, is most sensitive in the moderate range of cognitive impairment. It focuses on immediate recall and recognition aspects of memory rather than retention and delayed recall. As clinical trials for dementia continue to focus on prodromal stages of AD, instruments need to be retooled to focus on cognitive abilities more prone to change in the earliest stages of the disease. One such domain is delayed recall, which is differentially sensitive to decline in the earliest stages of AD. A supplemental delayed recall subtest for the ADAS-cog is commonly implemented, but we do not know precisely where along the spectrum of cognitive dysfunction this subtest yields incremental information beyond what is gained from the standard ADAS-cog. An item response theory (IRT) approach can analyze this in a psychometrically rigorous way. This study?s aims are twofold: (1) to examine where along the AD spectrum the delayed recall subtest yields optimal information about cognitive dysfunction, and (2) to determine if adding delayed recall to the ADAS-cog can improve prediction of functional outcomes, specifically patients? ability to complete basic and instrumental activities of daily living. Results revealed differential functioning of ADAS-cog subtests across the dimension of cognitive impairment. The delayed recall subtest provided optimal information and increased the ADAS-cog?s measurement precision in the relatively mild range of cognitive dysfunction. Moreover, the addition of delayed recall to the ADAS- cog, consistent with my hypothesis, increased covariation with instrumental but not basic activities of daily living. These findings provide evidence that the delayed recall subtest slightly improves the ADAS-cog?s ability to capture information about cognitive impairment in the mild range of severity and thereby improves prediction of instrumental functional deficits.Item Normal aging and Alzheimer's disease : hippocampal and episodic memory differences(2016-05) Marnell, Ashley Michele; Marquardt, Thomas P.; Henry, Maya LAlzheimer’s Disease (AD) and normal aging (NA) are characterized by structural brain changes as well as cognitive changes that appear over the lifespan. The hippocampus is an area susceptible to early atrophy in both AD and NA; however the differential causes of atrophy are not entirely clear. Hippocampal volume loss in AD is attributed to neuronal death due to underlying pathology. AD often is diagnosed years after the onset of pathology and subsequent atrophy. NA is a continuation of cognitive decline that does not become dementia. Episodic memory (EM) is processed within the hippocampus and is one of the first systems to show deficits in conjunction with both patterns of aging. This review focuses on hippocampal volume loss and EM decline in NA and AD.Item Profiling cerebrospinal fluid proteins in Alzheimer's disease(2011-08) Krishnamachari, Sesha; Tripathy, Jatindra Nath; San Francisco, Susan; Grammas, PaulaAlzheimer’s disease (AD) is a progressive, irreversible, neurodegenerative disease that affects more than 5 million people in USA alone and is expected to increase to 7 million by 2020. Currently, there are no drugs available that can halt or prevent the progression of this disease. This may be due to the complex nature of this disease with a number of proteins, mediators and factors involved or that there are some low abundance proteins not yet identified that may play a major role in the pathogenesis of AD. In this regard, with rapidly improving proteomics technologies it is possible to identify less abundant but potentially important functional molecules that may play an important role in the pathogenesis of AD. The objective of this study was to identify novel proteins expressed in the cerebrospinal fluid (CSF) of AD compared to age matched CSF samples from non-neurodegenerative cohorts. Using highly sensitive mass spectrometry techniques (MALDI-TOF/TOF), 260 protein spots from 18 AD and 14 control CSF samples were analyzed. Of the 141 proteins identified nine proteins were solely found in AD CSF but absent in the control CSF. Similarly eleven proteins identified in control CSF were not identified in AD CSF. Proteins identified include apolipoprotein E, cystatin C, orosomucoid, prostaglandin D2, enolase, and transthyretin. The results suggest that with proteomic profiling technology it will be possible to identify unique, low abundance proteins which may provide new insights into the pathogenesis of AD.Item Regulation of BACE1 promoter activity by nuclear factor-kappaB\r\n(2005-06-30) Krystyn Zimmer Bourne; J. Regino Perez-Polo; Steffen Rossner; Norbert K. Herzog; Kelly T. Dineley; Cheryl S. Watson; B. Mark EversThe brains of Alzheimer’s disease (AD) patients display cerebrovascular and parenchymal deposits of beta-amyloid peptides, which are derived by proteolytic processing of the amyloid precursor protein (APP). The beta-site APP-cleaving enzyme 1 (BACE1) is required for the generation of beta-amyloid peptides. The NF-kappaB binding DNA consensus sequence in the BACE1 promoter upstream of the gene’s transcription start site suggests a role for NF-kappaB in the expression of neuronal brain BACE1. Failure of activation of NF-kappaB responses to stress in the aged and disregulation of NF-kappaB in the AD brain may result in part in altered NF-kappaB regulation of BACE1 and alterations in cell specific BACE1 transcription and beta-amyloid protein processing.\r\n We identified a number of putative NF-kappaB transcription factor binding sites on the rat BACE1 promoter. The effects of NF-kappaB binding to the “primary” NF-kappaB binding site of the BACE1 promoter were stimulatory for activated astrocytic cells and repressive for neuronal cells. Age-associated perturbations of NF-kappaB activation may result in increasingly aberrant regulation of beta-amyloid processing by BACE1 via changes in the cellular levels of different NF-kappaB protein subunits and cumulative increases in astrocytically-derived beta-amyloid. We confirmed the observation that in PC12 cells the overall activity of NF-kappaB and BACE1 was significantly different depending on the apoptotic initiators: H2O2 or beta-amyloid. Our results are consistent with feedback mechanisms involving beta-amyloid exposure overriding NF-kappaB regulation of BACE1 over time, a source of negative feedback, consistent with observed neuropathologies. It is also likely that a series of transcription factor binding events determine which NF-kappaB binding sites are operant and this may explain the observed cell specificity of BACE1 regulation. Our observation that BACE1 expression was affected by both soluble and aggregated insulin, coupled with our previous observations that both aggregated Abeta1-42 and Abeta42-1 affected BACE1 expression, strongly suggest that the process of protein aggregation displayed by proteins sharing specific structural characteristics (i.e. zinc stabilized hexamers) may have pathological significance. It is tempting to hypothesize that insulin, and/or other similarly structured proteins, have effects on BACE1 activity that may play a role in the establishment and/or progression of Alzheimer’s disease. \r\nItem Role of aggregation conditions and presence of small heat shock proteins on abeta structure, stability and toxicity(Texas A&M University, 2006-08-16) Lee, Sung MunAlzheimer??s disease (AD) is a neurodegenerative disorder that is one of such diseases associated with protein aggregation. Aβ is the main protein component of senile plaques in AD, and is neurotoxic when aggregated. In particular, soluble oligomeric forms of Aβ are closely related to neurotoxicity. In this dissertation, we examine the differences in Aβ aggregation intermediates, and final structures formed when only a simple modification in Aβ aggregation conditions is made, the presence or absence of mixing during aggregation. We show that intermediates in the aggregation pathway show significantly different structural rearrangements. The protein stabilities of Αβ species show that spherical aggregates corresponding to the most toxic Αβ species change their structure the most rapidly in denaturant, and that in general, increased toxicity correlated with decreased aggregate stability. In Alzheimer??s disease, even delaying Aβ aggregation onset or slowing its progression might be therapeutically useful, as disease onset is late in life. Small heat shock proteins (sHsps) may be useful for prevention of Αβ aggregation, since sHsps can interact with partly folded intermediate states of proteins to prevent incorrect folding and aggregation. In this research, several small heat shock proteins (sHsps) are tested to prevent Aβ aggregation and toxicity. sHsps used in this research are Hsp17.7, Hsp27, and Hsp20. All types of Hsp20, Hsp20-MBP, His-Hsp20 and His-Hsp20 without 11 residues in C-terminus, can prevent Aβ1-40 aggregation. Hsp20 also prevents Aβ toxicity in the same concentration ranges of it aggregation prevention activity. Hsp17.7 and Hsp27, however, can inhibit Αβ1-40 aggregation but not toxicity. A number of experiments to examine the mechanism of Hsp20 suggest that multivalent binding of sHsp to Aβ is necessary for the toxicity prevention activity. Conclusively, different Aβ incubation conditions in vitro can affect the rate of Aβ fibril formation, the morphology, the toxicity and the conformation of intermediates in the aggregation pathway. Hsp20 rather than other sHsps may be a useful molecular model for the drug design of the next generation of Aβ aggregation inhibitors to be used in the treatment of AD.Item Self-complexity and family caregivers of Alzheimer's disease victims(Texas Tech University, 1991-05) Fankhauser, Betty LanierThere are strong indications that the elderly population of the United States is ever increasing in number. The most significant increase has been in those over age 85. This becomes particularly important when one considers the fact that Alzheimer's disease is for the most part a disease of the elderly. During the past decade, a great deal of interest has been shown in helping the caregivers of Alzheimer's disease patients deal with the oftentimes intense, long-term demands placed upon them while caring for victims of this basically unremitting disease. The present study was specifically interested in how the caregivers cope with stress-related burden and depression, with the special contribution of this study being the inclusion of Linville's self-complexity model. It is a model for examining self-complexity as a stress-related cognitive buffer or moderator variable. When in a multiplicative interaction with stress, self-complexity is hypothesized to provide a buffering effect on the adverse impact of stressful events. Participants were 74 adult family caregivers. The study involved two sessions, spaced a month apart, with the participants completing a packet of six instruments during each session. The participants reported life stresses, sense of burden, depression, and caregiver perception of patient level of functioning for the past month. In addition, they completed a measure of their self-complexity at each session. Four hypotheses were examined, using the data from the test periods. Preliminary analyses of self-complexity scores were quite close to those of Linville, However, when regression analyses were used, the results did not confirm Linville's previous research. The hypotheses testing did not support self-complexity as a stress-related buffer for family caregivers of Alzheimer's disease victims. The precise reasons for this are unclear, but multicollinearity appears to have been a limitation.