Dissertations / Theses on the topic 'Alzheimers’s disease'
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Holt, Jim. "Alzheimer’s Disease." Digital Commons @ East Tennessee State University, 2009. https://dc.etsu.edu/etsu-works/6482.
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梁欣珮 and Yan-pui Irene Leung. "Potential impact of alzheimer's disease on retina." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42905059.
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Holt, Jim, J. Guduru, and S. Pathi. "Alzheimer’s Disease, 2nd Revision." Digital Commons @ East Tennessee State University, 2015. https://dc.etsu.edu/etsu-works/6478.
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Holt, Jim, J. Guduru, M. Medipally, and S. Pathi. "Alzheimer’s Disease, 1st Revision." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/6480.
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Rickle, Annika. "PTEN and Akt signalling in Alzheimer's disease /." Stockholm : Karolinska institutet, 2005. http://diss.kib.ki.se/2005/91-7140-514-3/.
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Holt, Jim, Christopher T. Bridges, and Christian B. Potter. "Dementia (Alzheimer’s Disease), 3rd Revision." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/6472.
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Domingues, Catarina de Barros Pinto Salvador. "Chemokines impact in Alzheimer’s disease." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/16081.
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Mestrado em Biomedicina MolecularAlzheimer’s Disease (AD) is a neurodegenerative disorder neuropathologically characterized by the presence of extracellular senile plaques, intracellular neurofibrillary tangles and synaptic loss. Neuroinflammation has been associated with some neurodegenerative diseases, such as AD. In AD, increased Aβ production and aggregation, have a fundamental role in the activation of the inflammatory process. In turn, this could be fundamental in the early stages of this pathology, regarding the Aβ clearance and brain protection. However, chronic inflammation leads to an increase of the inflammatory mediators, such as cytokines, released by activated microglia, astrocytes, and neurons. The excessive production of these inflammatory components promotes alterations in both amyloid precursor protein (APP) expression and processing, stimulating the increase of Aβ accumulation and abnormal tau phosphorylation. This results in neurotoxic effects, irreversible damage and neuronal loss. Chronic inflammation is a feature of AD however, little is known about the effects of some chemokines on its pathogenesis. Thus, the main aim of this thesis was to study the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) on apoptosis, APP and tau. The both studied chemokines resulted in small alterations regarding the cytotoxicity on SH-SY5Y differentiated cells, being a significant increase in apoptosis observed only for the MCP-1 at the highest concentration. For the APP processing no significant differences were obtained, although a tendency to increase at different concentrations and periods was registered for both IL-8 and MCP-1. With respect to tau and other cytoskeleton-associated proteins, it was possible to observe a tendency to increase in the phosphorylated residue (Ser396) at the higher concentrations, as well as alterations on actin and tubulin with an increase on acetylated-α tubulin. This effect can be translated by neuronal architectural and survival alterations. Therefore additional studies could contribute to a better understanding of the way that these chemokines act on AD pathogenesis.
A Doença de Alzheimer (DA) é uma doença neurodegenerativa, caracterizada pela presença de placas senis extracelulares, tranças neurofibrilares intracelulares e perda sináptica. A neuroinflamação tem sido associada com algumas doenças neurodegenerativas, tal como a DA. Na DA, a produção e agregação aumentada do péptido Aβ, tem um papel fundamental na activação do processo inflamatório, que pode ser importante nas fases iniciais da doença, devido à remoção de Aβ e à proteção do cérebro. No entanto, uma inflamação crónica leva a um aumento de mediadores inflamatórios como são as citocinas, libertadas por microglia activada, astrócitos e neurónios. A produção excessiva de componentes inflamatórios promove alterações tanto na expressão como no processamento da proteína percursora amilóide (APP), levando a uma maior acumulação de Aβ e fosforilação anormal da proteína tau. Isto resulta em efeitos neurotóxicos, dano irreversível e perda neuronal. A inflamação crónica é uma característica da DA, no entanto pouco se sabe sobre os efeitos de algumas quimiocinas na sua patogénese. Assim, o principal objectivo desta tese foi o estudo do impacto da IL-8 e da MCP-1 na apoptose, APP e tau. Ambas as quimiocinas em estudo resultaram em pequenas alterações ao nível da citotoxicidade de células SH-SY5Y diferenciadas, tendo sido apenas observado um aumento significativo da apoptose para MCP-1 à concentração mais elevada. Relativamente ao processamento de APP, não foram observadas alterações significativas, no entanto alguma tendência para aumentar a diferentes concentrações e períodos foi obtida tanto para a IL-8 como para a MCP-1. Ao nível da tau e outras proteínas associadas ao citoesqueleto, foi possível observar uma tendência de aumento do resíduo fosforilado Ser396 às concentrações mais elevadas assim como alterações na actina e tubulina, com um aumento da αtubulina acetilada. Este efeito pode ser traduzido em alterações na arquitetura e sobrevivência neuronal. Assim sendo, estudos adicionais podem contribuir para uma melhor compreensão do modo de ação destas quimiocinas na patogénese da DA.
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Barra, Cátia Isabel de Almeida. "Inflammatory biomarkers in Alzheimer’s disease." Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13277.
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Mestrado em Biomedicina MolecularAlzheimer’s disease (AD) is the most common form of dementia. Histopathologically it is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFT) and the extracellular senile plaques (SP), which are surrounded by activated astrocytes and microglia. Neuroinflammation has been associated with some neurodegenerative diseases. In AD the inflammatory process, prompted by increased Aβ production and aggregation, was reported to have a fundamental role in disease pathogenesis. In early stages the inflammation could have a beneficial role in the pathology, since it has been proposed that the microglia and astrocytes activated could be involved in (amyloid β) Aβ clearance. Nevertheless, the chronic activation of the microglia leads to excessive production of the inflammatory components, including cytokines. It promotes alterations in amyloid precursor protein (APP) expression and processing, stimulating the increase of Aβ accumulation, abnormal Tau phosphorylation and, consequently, neurotoxic effects, irreversible damage and loss of neurons. Since chronic neuroinflammation is a feature of AD, inflammatory proteins may constitute potential biomarkers candidates to assist clinical diagnosis of this dementia. Thus, the main aim of this study was to identify putative inflammatory biomarkers for AD by flow citometry analysis. For plasma samples of individuals examined by clinical dementia rating (CDR) and mini mental (MM) diagnostic tests were used. Subjects were subdivided in 3 distinct groups, a control group (CDR-/MM-) and two patient groups, CDR+/MM- and CRD+/MM+, the former may include mild cognitive impairment (MCI) patients and the latest group included 5 patients clinical diagnosed as AD. Data analysis revealed differences in the inflammatory proteins levels of both patients groups (CDR+/MM- and CDR+/MM+) in comparison to healthy individuals (CDR-/MM-). Interleukin-8 (IL-8) plasma levels were statistically different (P<0,05) from control group. Significant correlation between IL-8 concentrations and the CDR stages was also identified. Additionally, correlations of monocyte chemoattractant protein-1 (MCP-1) with both IL-8 and IL-6 were observed. Taken together these findings suggested that IL-8 could be a potential biomarker not only for AD but also for diagnosis of initial stages of dementia.
A doença de Alzheimer (DA) é o tipo de demência mais comum. Histopatologicamente é caracterizada pela presença de tranças neurofibrilares intracelulares (TNF) e de placas senis extracelulares (PS), as quais estão rodeadas pela microglia e por astrócitos. A neuroinflamação tem sido associada com várias doenças neurodegenerativas. Na DA o processo inflamatório, desencadeado pelo aumento da produção e agregação do péptido Aβ, desempenha um papel fundamental na patogénese da doença. Nas fases inicias, a inflamação possui um papel benéfico na patologia, uma vez que tem sido proposto que a microglia e os astrócitos quando ativados estão envolvidos na remoção de β-amilóide (Aβ). No entanto, a ativação crónica da microglia conduz à produção excessiva de componentes inflamatórios, incluindo citocinas. Isto provoca alterações na expressão e processamento da proteína percursora de amilóide (PPA), estimulando o aumento da produção e acumulação de Aβ, fosforilação anormal da proteína Tau e, consequentemente, efeitos neurotóxicos e perda de neurónios. Uma vez que a neuroinflamação crónica é uma característica da DA, proteínas inflamatórias poderão constituir potenciais candidatos a biomarcadores que auxiliem no diagnóstico clínico desta doença. Desta forma, o principal objectivo deste trabalho foi identificar biomarcadores inflamatórios para a DA através da técnica de citometria de fluxo. Para tal, foram analisadas amostras de plasma de doentes que foram, previamente, examinados por testes de avaliação cognitiva, clinical dementia rating (CDR) e mini mental (MM). Os sujeitos foram divididos em três grupos distintos, o grupo controlo (CDR-/MM-) e dois grupos de pacientes, CDR+/MM- e CDR+/MM+. O primeiro grupo de pacientes pode conter indivíduos com ligeiras alterações cognitivas (MCI) e o segundo inclui 5 pacientes clinicamente diagnosticados para DA. A análise dos dados revelou diferenças nos níveis de proteínas inflamatórias de ambos os grupos de doentes (CDR+/MM- e CDR+/MM+) em comparação com os indivíduos saudáveis (CDR-/MM-). Os níveis plasmáticos de interleucina-8 (IL-8) foram estatisticamente deferentes (p<0,05) do grupo controlo. Correlação significativa entre as concentrações de IL-8 e os estados de CDR foi identificada. Adicionalmente, foram observadas correlações entre MCP-1 e IL-8 e a IL-6. Em conjunto, estes resultados sugerem que a IL-8 poderá ser um potencial biomarcador não só para a DA mas também para o diagnóstico precoce de demência.
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Navaratnam, Dasakumar Selveraj. "Cholinesterases in Alzheimer's disease." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306734.
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Newman, Tracey Anne. "Ageing and Alzheimer's disease." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246220.
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Montacute, Rebecca. "Infection in Alzheimer's disease." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/infection-in-alzheimers-disease(a69fbf77-1455-4a78-a700-54815cad926d).html.
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Infections are a common co-morbidity in Alzheimer's disease (AD), and evidence suggests that infections can exacerbate neuroinflammation and increase cognitive decline in AD patients. In AD, immune changes are observed both in the central nervous system (CNS) and in the rest of the body. However, only a few studies have investigated immune responses to infection in AD. Here, two extensively studied infections, Toxoplasma gondii (T. gondii) and Trichuris muris (T. muris) were used to investigate infection in AD. T. gondii is a protozoan parasite which is common globally, including in the developed world where AD cases are increasing dramatically. Infection with T. gondii starts in the gut, before becoming systemic and then infecting the CNS, where the parasite forms a chronic cyst infection. In contrast, T. muris is a nematode parasite, which remains localised to the gut. Notably, T. gondii is known to alter neuroinflammation and behaviour. T. gondii forms cysts preferentially in the areas of the brain commonly affected by AD, such as the hippocampus, which therefore makes it an interesting model to study co-morbidity. AD is often associated with advanced age. As we age, our immune system declines, and an important unanswered question is whether age impacts on the immune response to infection. This is of particular significance when considering chronic infections such as T. gondii, which require immune surveillance to prevent parasite recrudescence. Therefore, the aim of this thesis was to investigate infection in AD by determining: whether the immune response to an infection is altered in AD; whether the immune response to an infection in AD differs with age; what the effects of infection are on neuroinflammation, pathology and behaviour in AD; what are the effects of chronic infection with T. gondii. Immune responses to infection were altered in both the 3xTg-AD and the APP PS1 mouse models of AD, including increased inflammation and weight loss in AD mice following infection. Although older (eleven to twelve-month-old) 3xTg-AD mice showed some alterations in cytokine responses following infection, overall there were no major difference compared to younger (five to six-month-old) animals. Additionally, infection was found to alter neuroinflammation in both 3xTg-AD and APP PS1 mice, though differently. In 3xTg-AD mice, microglia activation increased following infection with T. gondii and T. muris, showing that infection did not need to be in the brain to alter neuroinflammation. In APP PS1 mice, a decrease in microglia activation occurred after infection with T. gondii, which was accompanied by an increase in IL-1alpha production and increased amyloid beta levels in APP PS1 mice following infection. However, no changes were found in behaviour following infection with T. gondii or T. muris in AD mouse models. Finally, chronic T. gondii infection was investigated in the TgF344-AD rat, which was established as a suitable AD model with both amyloid and tau pathology in which to study chronic infection. This work adds to a growing body of literature to suggest that infections are detrimental to AD patients, and that future measures to decrease morbidity could focus on further study of infections in AD, and the development of strategies to better prevent infections in AD patients.
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Zubair, Mohammed. "Metabolomics in Alzheimer's disease." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/metabolomics-in-alzheimers-disease(0872757b-d25a-4c43-bd52-915d4cad21c6).html.
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Metabolites are a potentially useful source of detecting and identifying disease specific biomarkers. This thesis investigates the possibility of using metabolomics applications to detect Alzheimer’s disease associated metabolite peaks in patients and to detect longitudinal changes of the disease. Serum samples and clinical data were collected from 60 healthy controls and 60 Alzheimer’s disease patients (60 at baseline and 60 at 12 month follow-up). The metabolic fingerprinting of serum samples using the FT-IR lacked discriminatory power to discriminate Alzheimer’s disease and non-disease samples due to the similar magnitude of biological and analytical variation. The metabolic profiling of serum samples using the GC-ToF-MS did not reveal any significantly altered metabolite peaks between the Alzheimer’s disease and non-disease groups. Metabolic profiling of serum samples using the UPLC-LTQ/Orbitrap-MS operated in the positive ionisation mode did not reveal any significantly altered metabolite peaks between the disease and non-disease groups. Up to twelve metabolite peaks were significantly altered in the Alzheimer’s disease baseline and follow-up samples, indicating a potential association with disease progression. Metabolic profiling of serum samples using the UPLC-LTQ/Orbitrap-MS operated in the negative ionisation mode did not reveal any significantly altered metabolite peaks between Alzheimer’s disease and non-disease groups. Three metabolite peaks were significantly altered in the Alzheimer’s disease baseline and follow-up samples, indicating a potential association with disease progression. Metabolic profiling of serum samples with the UPLC-LTQ/Orbitrap-MS may potentially be used to detect disease and disease progression associated metabolite peaks. The metabolite peaks require identification followed by a validation experiment.
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Shie, Feng-Shiun. "Cholesterol and Alzheimer's disease /." Thesis, Connect to this title online; UW restricted, 2000. http://hdl.handle.net/1773/6604.
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Roberts, Cathryn Emma Yorath. "Emotion and alzheimers disease." Thesis, Bangor University, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.506173.
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Fokuoh, Evelyn, and Kesheng Wang. "A linear mixed model analysis of the APOE4 gene with the logical memory test total score in Alzheimer’s disease." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/211.
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Linear mixed model (LMM) has the advantage of modeling the corelated data. Alzheimer’s disease (AD) is a chronic neurogenerative disease that affects the brain of the subject. No study was found to study the longitudinal effect of apolipoprotein E epsilon 4 (APOE4) genotype on the logical memory test total score in AD. A longitudinal data of 844 with AD, 2167 with cognitive normal (CN), and 4472 with mild cognitive impairment (MCI) participants who underwent logical memory examination test in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were investigated. Episodic memory of the study participants was monitored based on a short story told to the participants and then participants asked to recall what was told. The multivariate LMM was used to determine the longitudinal changes in the logical memory test total score adjusting for age and sex. The Akaike information criterion (AIC) statistic and the Bayesian information criterion (BIC) statistic were used to select the best covariance structure. The repeated measures longitudinal analysis was performed using PROC MIXED in SAS 9.4. Both AIC and BIC statistics favor the unstructured correlated structure (UN). Using a UN model in the LMM, the APOE gene was is significantly associated with logical memory test total score (pUN covariance structure is the best. This study provided the first evidence of the effect of APOE4 genotype on the logical memory related to AD.
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Arendt, Thomas, Martina K. Brückner, Markus Morawski, Carsten Jäger, and Hermann-Josef Gertz. "Early neurone loss in Alzheimer’s disease." Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-160935.
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Alzheimer’s disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for
more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assesses neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.
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Carbone, Ilaria <1984>. "Human herpes virus and Alzheimer’s disease." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5255/.
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Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder and according to the WHO it is estimated that 36 millions of people worldwide currently suffer from AD. Genetic and environmental factors interact in a complex interplay that might affect pathogenic mechanisms leading to age-related neurodegeneration. The hypothesis is that the presence of allelic polymorphisms in selected genes affecting individual brain susceptibility to infection by the herpes virus family during aging, may contribute to neuronal loss, inflammation and amyloid deposition. Herpes virus family show features relevant to AD, since they infect a large proportion of human population, develop a latent form persisting for several years, are difficult to eliminate by immune responses especially when latency has been established and are able to infect neurons. The association between AD and herpes viruses infection has been investigated. In particular the investigation focused on CMV, EBV and HHV-6 in DNA samples from peripheral blood of a large cohort of patients with clinical diagnosis of AD and age matched CTR, from a longitudinal population study, and DNA samples from brain tissue of patients with neuropathological diagnosis of definitive AD. An association between the presence of EBV and HHV-6 DNA from PBL positivity with the cognitive deterioration and progression to AD has been focused. Moreover, IgG plasma levels in CTR and AD to these viruses were tested. CMV and EBV IgG plasma levels were higher in elderly subjects that developed clinical AD at the end of the five year follow up. Our findings support the notion that persistent cycles of latency and reactivation of herpes viruses may contribute to impair systemic immune response and induce altered inflammatory process that in turn affect cognitive decline during aging.
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Schroeder, Sulana Kay. "Tau-Directed Immunotherapy for Alzheimer’s Disease." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6757.
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Alzheimer’s disease (AD) is the leading cause of dementia, accounting for 50 to 80 percent of dementia cases, and the prevalence of the disease is projected to increase significantly with time. AD is characterized by severe cognitive decline with age, ultimately requiring continued caregiving and eventually death. The pathology of AD is characterized by the presence of extracellular amyloid plaques, intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein, neuron loss, and evidence of inflammation indicated by the presence of reactive microglia and astrocytes. Frontotemporal Lobe Dementia (FTLD) is a rare form of dementia that is related to AD, most notably in the pathology of hyperphosphorylated tau and macroscopic brain shrinkage. It has been defined as one of a host of tauopathies, and has a more rapid onset than AD. Symptoms that resemble personality changes, moreso than memory loss, are characteristic of these other tauopathies (FTLD is a representative of a whole class of neurological disorders). Like AD, there are no known treatments or cures for FTLD. AD and FTLD are two manifestations of a class of diseases known as tauopathies, due to the presence of toxic forms of tau.
Tau is a protein normally found in neurons. It functions as a stabilizer for microtubules, and has a role in the trafficking of materials from the cell body to the presynaptic terminal. In AD and FTLD, tau can become hyperphosphorylated, which causes it to form twisted fibrils called NFTs. An emerging area of research is to identify antibodies that target tau as a way to clear tau pathology and hopefully reduce synaptic and neuron loss (Boutajangout et al., 2011b). While these diseases have no known cure or treatment at present, immunotherapy is emerging as a promising approach for treatment. The studies presented here investigated a variety of antibodies directed against tau, and incorporated different timeframes and administration routes to identify the best candidate for future clinical investigation of tau immunotherapy.
The mouse model rTg4510, known for expressing cognitive-related tauopathy, was primarily used to evaluate tau antibody effectiveness prior to clinical consideration. Our investigations began by utilizing a more familiar mouse which was also reported to express tau pathology.
Our studies first examined intracranial injection of a variety of antibodies using a mouse model previously reported to demonstrate tau pathology, to identify short-term clearance of tau pathology and NFTs. Next, we examined a more robust tau-producing mouse line, to further identify a most effective antibody, as well as to examine the time course of effect, after administration. A longer-term administration, and different route of administration was tested using mini-osmotic pump implantation into the mice, which provided for 28-day continuous infusion. This approach was followed with administration of antibodies, systemically. Behavioral analysis, in addition to pathological testing, was incorporated into the longer-term administration studies.
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Wang, Juelu. "Selective neurodegeneration in Alzheimer's disease and Parkinson's disease." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63267.
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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are featured by cholinergic and dopaminergic neuron loss, respectively. As a unique pathological hallmark of AD, neuritic plaques contain aggregated amyloid β protein (Aβ), generated from amyloid β precursor protein (APP). APP mutations cause familial AD; mutations in the alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with PD.
Recent studies suggest that the level of LRRK2 affects its toxicity in neurons. Therefore, understanding the mechanisms underlying LRRK2 expression would help to examine its pathogenic effects on PD. However, the features of the LRRK2 promoter remain elusive. In the first project, we cloned and characterized the LRRK2 promoter. There were two functional cis-acting specificity protein 1(Sp1)-responsive elements in its promoter. Our study demonstrates that LRRK2 transcription and translation were facilitated by Sp1 overexpression and blocked by an Sp1 inhibitor in vitro.
The Lewy bodies primarily consist of α-synuclein protein, encoded by SNCA, and SNCAA₅₃T mutation promotes α-synuclein aggregation. The Swedish APP mutation (APPSWE) promotes Aβ generation and AD pathogenesis. However, the mechanisms underlying selective neurodegeneration in AD and PD are still unknown. In the second project, we stably overexpressed wildtype and mutated APP and SNCA genes in cholinergic SN56 and dopaminergic MN9D cells. APPSWE and SNCAA₅₃T mutations enhanced Aβ generation and α-synuclein inclusion formation in SN56 and MN9D cells, respectively. Aβ₄₂ and mutant α-synuclein oligomers caused severe cell death in SN56-APPSWE and MN9D-SNCAA53T cells, respectively. Furthermore, syndecan 3 (SDC3) and fibroblast growth factor receptor like 1 (FGFRL1) genes were identified as two of the differentially expressed genes in APP- and SNCA- related stable cells by microarrays. SDC3 was increased in the cholinergic nucleus of APPSWE knock-in mouse brains, whereas FGFRL1 was elevated in dopaminergic neurons in SNCAA₅₃T transgenic mice. Finally, knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA₅₃T cells. Overall, these demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA₅₃T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.Medicine, Faculty of
Graduate
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Kanju, Patrick M. Suppiramaniam Vishnu. "Synaptic glutamate receptor dysfunction in tissue and animal models of Alzheimer's disease." Auburn, Ala., 2005. http://repo.lib.auburn.edu/2005%20Summer/doctoral/KANJU_PATRICK_11.pdf.
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Hynd, Matthew. "Excitotoxic neurodegeneration in Alzheimer's disease /." [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18145.pdf.
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Blom, Elin. "Genetic Studies of Alzheimer's Disease." Doctoral thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9397.
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Patients with Alzheimer's disease (AD) often have a family history of the disease, implicating genetics as a major risk factor. Three genes are currently known to cause familial early-onset AD (<65 years): the amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2). For the much more common late-onset disease (>65 years), only the APOE gene has repeatedly been associated to AD, where the ε4 allele increases disease risk and decreases age at onset. As APOE ε4 only explains part of the total estimated disease risk, more genes are expected to contribute to AD. This thesis has focused on the study of genetic risk factors involved in AD. In the first study, we conducted a linkage analysis of six chromosomes previously implicated in AD in a collection of affected relative pairs from Sweden, the UK and the USA. An earlier described linkage peak on chromosome 10q21 could not be replicated in the current sample, while significant linkage was demonstrated to chromosome 19q13 where the APOE gene is located. The linkage to 19q13 was further analyzed in the second study, demonstrating no significant evidence of genes other than APOE contributing to this peak. In the third study, the prevalence of APP duplications, a recently reported cause of early-onset AD, was investigated. No APP duplications were identified in 141 Swedish and Finnish early-onset AD patients, implying that this is not a common disease mechanism in the Scandinavian population. In the fourth study, genes with altered mRNA levels in the brain of a transgenic AD mouse model (tgAPP-ArcSwe) were identified using microarray analysis. Differentially expressed genes were further analyzed in AD brain. Two genes from the Wnt signaling pathway, TCF7L2 and MYC, had significantly increased mRNA levels in both transgenic mice and in AD brains, implicating cell differentiation and possibly neurogenesis in AD.
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Bakerink, Ronda Ann. "Semantic memory in Alzheimer's Disease." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/27795.
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Alzheimer's Disease is characterized by a general decline in cognitive functioning. Although phonology are relatively unaffected, patients with Alzheimer's Disease have been reported to have deficits of semantic memory. Thirteen patients with dementia, five of whom had a confirmed diagnosis of dementia, participated in the study. The purpose of this investigation was to replicate a study performed by Mark Byrd (1984), using Alzheimer's Disease patients. Subjects were presented with category-word decision pairs, for which the task was to decide if the word was an exemplar of the category, and category-letter decision pairs for which the task was to generate an exemplar of the category beginning with the letter. The dependent variable was reaction time.
Results indicated that Alzheimer's Disease patients and dementia patients had longer reaction times than a group of age-matched control subjects, and that the Alzheimer's Disease and dementia patients showed a pattern of responses similar to that of the control subjects. All groups showed longer reaction times for the generation trials than the decision trials. The results are consistent with the existence of a semantic memory deficit in Alzheimer's Disease, but other interpretations were discussed.Medicine, Faculty of
Audiology and Speech Sciences, School of
Graduate
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Williams, Abigail J. "Cystatin C and Alzheimer's disease." Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/8547/.
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Aggregation of amyloid-β in Alzheimer's disease (AD) is modulated in the presence of other amyloidogenic proteins including human cystatin C (hCC), which directly protects neuronal cells from Aβ-induced toxicity and inhibits fibril formation. Determination of the relevant conformations of the interacting Aβ and hCC is a key step to uncovering the molecular mechanism of hCC's activity in AD. A system for the production of recombinant Aβ1-40 has been established and is described here. It is also shown that hCC readily produces stable oligomeric species upon incubation in aggregating conditions, a phenomenon that has not been observed for other members of the cystatin family. Novel structural differences between amyloid fibrils produced by hCC and cystatin B have also been identified using limited proteolysis, indicating that hCC does not retain a monomer-like fold within the fibril and that the N-terminal is disordered and not part of the fibril core. The work presented here shows that hCC inhibits fibril production by Aβ in a dose-dependent manner, instead promoting the production of amorphous aggregates and small assemblies, with 2:1 molar ratios of hCC to Aβ being required for complete inhibition. It is unclear if the assemblies observed are toxic protofibrils or an alternative non-toxic species. A comparison of the inhibitory activity of the monomeric and dimeric forms of hCC was carried out, and indicated that the active region could be the hydrophobic loop involved in protease inhibition. Characterisation of binding by NMR HSQC experiments revealed that no observable complex was being formed between monomeric Aβ and folded monomeric hCC. Taken together these results suggest that hCC is selectively binding to an oligomeric species of Aβ and trapping the peptide in a non-toxic state.
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Beffert, Uwe. "Apolipoprotein E in Alzheimer's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0021/NQ55300.pdf.
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Bothmer, John. "Phosphoinositides, aging and Alzheimer's disease." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1992. http://arno.unimaas.nl/show.cgi?fid=6504.
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Howell, Walter Mathias. "SNP technology and Alzheimer's disease /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-473-9/.
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Naidj, Sonia. "Visuospatial dysfunction in Alzheimer's disease." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23924.
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The objective of this study was to identify subgroups in patients with Alzheimer's Disease (AD), based on a dissociation in their performance on visuospatial tasks: one subgroup with predominant impairment on object recognition or the "What" system, and another subgroup with predominant impairment in spatial recognition or the "Where" system. Also, an attempt was made to clarify the relationship between attention on these two visuospatial processes. Amongst twenty-four patients with AD, we identified two pairs of patients with dissociated performances. However, except for one case, the dissociations found were mainly based on the prominent impairment of the spatial ability or the "Where" system. Based on the performance of cohort, our results suggested that spatial abilities are more impaired than the object recognition ability. In addition the results showed that AD also affects the central executive system, and that the impairments in visuospatial processes, especially the "What" system, may at least partly be explained by deficits in this system. These findings also indicate that certain sub-components of visuospatial processes can be distinctively affected by AD.
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Xu, Chun. "Morphological subtypes of Alzheimer's disease." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=61223.
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Initiating a computerized population-based registry of Alzheimer's disease (AD), the IMAGE Project has developed a multimatrix model to investigate the disease. Part of the IMAGE Project 1, the neuropathological study, is designed to correlate clinical, neuropsychological and neuropathological features of AD for characterization of subtypes. This thesis reports mainly the morphometrical studies associated with project 1.The study, based on (a) brain autopsy, (b) standardized histopathology, and (c) quantitative morphometry, shows heterogeneity in pathophenotypes of AD. Four morphological subgroups have been presently recognizes, by their characteristic histological abnormalities, and the densities, the distribution, and progression patterns of their lesions. The heterogeneity in pathophenotypes indicates that AD is not a disease with a single cause, but rather a syndrome with multiple elements involved in etiology and pathogenesis. These lead to different pathological features, and correspondingly, similar, but distinguishable clinical expressions.
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Spillantini, Maria Grazia. "Molecular neuropathology of Alzheimer's disease." Thesis, University of Cambridge, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282037.
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Bourne, Nathan T. "Molecular mechanisms of Alzheimer's disease." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521906.
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Smith, M. A. "Protein structures and Alzheimer's disease." Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.291081.
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Treanor, James J. S. "Neurotrophic factors and Alzheimer's disease." Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385730.
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Bucks, Romola Starr. "Intrusion errors in Alzheimer's disease." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285578.
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Fox, Sarah. "Oscillations memory and Alzheimer's disease." Thesis, University of Manchester, 2014. https://www.research.manchester.ac.uk/portal/en/theses/oscillations-memory-and-alzheimers-disease(bbacb2f0-74f3-4071-b02f-19c0c5570227).html.
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Damage precipitating cognitive decline in Alzheimer's disease (AD) begins long before behavioural alterations become clinically apparent. At this prodromal stage, communication between networks of neurons connecting different brain regions starts to break down; setting in motion a chain of events leading to clinical AD. A significant challenge facing Alzheimer's researchers today is finding a cheap, easy-to-perform test capable of detecting prodromal AD. Such a test would afford significant benefits to patients, including a chance of early intervention. Perhaps, more importantly, it would also aid development and testing of novel therapies aimed at combating AD before it causes irreversible damage. Since oscillations in electrical field activity are important for facilitating connectivity across the brain and have been seen to alter in AD, this work studied how oscillations and regional connectivity are affected in the AD brain. Specifically, local field oscillations were recorded from the hippocampus and prelimbic cortex (regions implicated in memory formation and maintenance) in a double transgenic AD model - the TASTPM mouse. Here, periods of predominant theta activity were assessed both spontaneously, under urethane anaesthesia and following electrical induction through dorsal periaqueductal gray (dPAG) stimulation. From these recordings, spectral power and connectivity between regions was assessed using both a traditional measure of functional connectivity (inter-region correlation) and through a novel information theoretic approach measuring effective connectivity (transfer entropy).Perhaps the most prominent finding from this study was the observation that young TASTPM mice, at an age prior to overt cognitive decline or plaque deposition, showed significant alterations in measures of both functional and effective connectivity. This suggests that such measures may be used as biomarkers predictive of prodromal AD and, as such, may be used to aid development of drugs targeted towards treatment of prodromal AD.This study also uncovered a number of interesting observations concerning hippocampal/prelimbic connectivity. Firstly, although spectral power and inter-regional correlation peaked at ∼ 3Hz, information flow between these structures was strongest at ∼6Hz. This suggests that low and high-band theta activity may fulfil separate functions. Secondly, at theta frequencies, information flowed predominantly from the prelimbic cortex to the hippocampus. However, during lower frequency activity, information flowed predominantly in the opposite direction. Suggesting that separate frequency bands may be important for routing information flow between these structures. Finally, the strength of information transfer was seen to oscillate at approximately double the frequency of its carrier signal, perhaps suggesting locking of information transfer to certain phases of an underlying oscillation. Therefore, oscillations may structure information transfer by temporal windowing and frequency-locked routing; processes which can be studied using measures of effective connectivity such as transfer entropy.
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Benjamin, Maxwell J. "Autobiographical memory in Alzheimer's Disease." Thesis, Canterbury Christ Church University, 2013. http://create.canterbury.ac.uk/12348/.
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Retrieval of autobiographical memories (AMs) is important for “sense of self”. Current theoretical understanding of AM retrieval predicts that working memory (WM) and executive functions (ExF) enable the hierarchical search for, and reliving of past, personal events in the mind’s eye. However, there remains a lack of consensus as to the nature of the relationships between these cognitive functions and semantic and episodic aspects of AM. The present study therefore aimed to explore the associations between these variables in a sample with a wide range of ability on measures of WM, ExF, and AM. The study incorporated a between-groups component, and a correlational component with regression and mediation modelling. Participants with Alzheimer’s disease (n = 10) and matched healthy controls (n = 10) were assessed on measures of semantic and episodic AM search and retrieval, auditory and spatial WM, and verbal fluency. AD group AMs were significantly less episodic in nature compared to controls. There were no significant associations between WM measures and hierarchical search of semantic AM, or episodic AM retrieval. Verbal fluency, but not WM, predicted episodic AM retrieval and mediated the effect of dementia status on episodic AM retrieval independent of age effects. The study concluded that people with AD may be limited in their retrieval of episodic AM due to weaker verbal fluency, independent of ageing effects. WM appeared to play little role in facilitating episodic AM retrieval. Reminiscence interventions for people with AD might benefit from incorporating structured, individualised external memory-aids to facilitate more effective AM search and retrieval to prolong wellbeing.
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Davidson, Madeiene E. "Alzheimer's Disease: The Triple Threat." Scholarship @ Claremont, 2016. http://scholarship.claremont.edu/cmc_theses/1287.
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Many Americans know Alzheimer’s disease for its devastating physical, emotional, and financial impact on patients as well as their family members and friends. According to the Alzheimer’s Association’s recent national survey, 73 million voters have had a family member or friend with the disease, indicating that the nation is aware of the disease’s affect on patients, their relatives, friends, and caretakers.
Many are unaware, however, that Alzheimer’s could impose an enormous economic burden on the nation. Harry Johns, the president and CEO of the Alzheimer’s Association, calls Alzheimer’s “a triple threat unlike any other disease with its soaring prevalence, lack of treatment and enormous cost.” Nearly 5.3 million Americans are currently diagnosed with this untreatable disease. As the elderly continue to age, the demand for government aid in the form of Medicare and Medicaid will increase. This increasing demand, along with the decline in the labor force participation rate, will increase costs to all those affected by Alzheimer’s in the coming decades.
The federal government has assumed leadership in the fight against Alzheimer’s by passing legislation to secure funding and establish a timeline for research, engage stakeholders, and provide support for Alzheimer’s patients, families, and caregivers. This thesis offers a holistic view of the current challenges facing the Alzheimer’s community, including costs of the disease to patients, families, and to society. It also includes an overview of Alzheimer’s legislation that addresses these challenges and provides a budget for scientific research for a treatment or a cure in the next decade to prevent the impending national fiscal catastrophe. This thesis will provide recommendations for how policy makers can decrease the likelihood that the federal government will be forced to pay the projected cumulative $20 trillion total cost of Alzheimer’s disease and other dementias by 2050. This thesis also recommends ways to provide immediate support the growing number of caregivers to Alzheimer’s patients.
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Kim, Sohee. "Computational modeling in Alzheimer's disease." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1267541374.
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Huseby, Carol. "Molecular Neuropathology in Alzheimer's Disease." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1543314678552794.
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Morshed, Nader Francis. "Phosphoproteomics analysis of Alzheimer's disease." Thesis, Massachusetts Institute of Technology, 2021. https://hdl.handle.net/1721.1/130816.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, February, 2021Cataloged from the official PDF version of thesis.
Includes bibliographical references (pages [137]-[153]).
Alzheimer's disease (AD) is a form of dementia characterized by the appearance of amyloid-[beta] plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Despite numerous clinical trials, a limited understanding of disease pathogenesis has prevented the development of effective therapies. Several lines of genetic and biomolecular evidence indicate that AD progression involves cellular signaling through neuronal and glial protein phosphorylation networks. In order to understand which phosphorylation networks are dysregulated, I use mass spectrometry to characterize the phosphoproteome of post-mortem brain tissue from AD patients and multiple mouse models of AD. Using computational analysis, I identified several signaling pathways that are dysregulated before neurodegeneration occurs. Many of these signaling factors were expressed primarily in non-neuronal cell types, including microglia, astrocytes, and oligodendrocytes.
My results highlight potential therapeutic targets in the signaling responses of glial cells and are split into two parts. In the first part of this thesis, I have quantified the phosphoproteome of the CK-p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. I identified a shared response involving Siglec-F which was upregulated on a subset of reactive microglia. The human paralog Siglec-8 was also found to be upregulated on microglia in AD. Siglec-F and Siglec-8 were upregulated following microglial activation with interferon gamma (IFN[gamma]) in BV-2 cell line and human stem-cell derived microglia models. Siglec-F overexpression activates an endocytic and pyroptotic inflammatory response in BV-2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine-based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV-2 cells.
Collectively, my results point to an important role for mouse Siglec-F and human Siglec-8 in regulating microglial activation during neurodegeneration. In the second part of this thesis, I performed a combined analysis of the tyrosine, serine, and threonine phosphoproteome, and proteome of temporal cortex tissue from AD patients and aged matched controls. I identified several co-correlated peptide modules that were associated with varying levels of Tau, oligodendrocyte, astrocyte, microglia, and neuronal pathologies in different patients. I observed phosphorylation sites on known Tau-kinases and other novel signaling factors that were correlated these peptide modules. Finally, I used a data-driven statistical modeling approach to identify individual peptides and co-correlated signaling networks that were predictive of AD pathologies. Together, these results build a map of pathology-associated phosphorylation signaling events occurring in AD.
by Nader Francis Morshed.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
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Townsend, Kirk Phillip. "Microglia activation in Alzheimer's disease." [Tampa, Fla.] : University of South Florida, 2004. http://purl.fcla.edu/fcla/etd/SFE0000489.
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Morris, Eva Marie. "Semantic Memory in Alzheimer's Disease." W&M ScholarWorks, 1999. https://scholarworks.wm.edu/etd/1539626235.
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Vasseur, Janis S. "The geographical implications of Alzheimer's disease : an examination of the impact that Alzheimer's disease hs on family caregivers in Connecticut /." Abstract Full Text (PDF), 2008. http://eprints.ccsu.edu/archive/00000509/02/1965FT.pdf.
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Thesis (M.S.) -- Central Connecticut State University, 2008.Thesis advisor: Cynthia Pope. "... in partial fulfillment of the requirements for the degree of Master of Science in Geography." Includes bibliographical references (leaves 85-90). Also available via the World Wide Web.
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Lane, Fiona Mary. "Defining mechanisms of neurodegeneration associated with protein misfolding diseases." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/19542.
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Protein misfolding diseases (PMDs) are a broad group of disorders including Alzheimer’s, Parkinson’s and prion diseases. They are characterised by the presence of aggregated, misfolded host proteins which are thought to cause cell death. Prion diseases are associated with misfolded prion protein (PrPSc), which has a tendency to form fibrillar aggregates. By contrast, Alzheimer’s disease (AD) is associated with misfolded amyloid beta (Aβ), which aggregates to form characteristic Aβ plaques. A feature which is common across PMDs is that small assemblies (oligomers) of the misfolded proteins are thought to be the important neurotoxic species, and it has been proposed that there may be a shared mechanism leading to cell death across PMDs caused by oligomers. In this study, the toxicity of different misfolded forms of recombinant PrP (recPrP) and recombinant Aβ (recAβ) and the mechanisms leading to cell death were investigated using a primary cell culture model. In addition, the importance of the disulphide bond in recPrP in relation to oligomer formation was explored using size exclusion chromatography and mass spectrometry, the toxicity of the different resulting oligomer populations were also investigated. Both recPrP oligomers and fibrils were shown to cause toxicity to mouse primary cortical neurons. Interestingly, oligomers were shown to cause apoptotic cell death, while the fibrils did not, suggesting the activation of different pathways. By contrast, recAβ fibrils were shown to be non-toxic to cortical neurons, Aβ oligomers, however, were shown to cause toxicity. Similar to recPrP, my data showed that it is likely that recAβ 1-42 oligomers also cause apoptosis. However, by contrast this seemed to be caused by excitotoxicity, which was not found to be the case for recPrP. Additionally, I have shown that the presence or absence of the disulphide bond in PrP has a profound effect on the size of oligomers which form. RecPrP lacking a disulphide bond leads to the formation of larger oligomers which are highly toxic to primary neurons. Findings from this study suggest that structural properties such as the disulphide bond in PrP can affect the size and toxicity of oligomers, furthermore, whilst oligomers have been shown to be important in both AD and prion diseases, they may not trigger the same pathways leading to cell death.
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Fisher, Linda. "Inflammatory cytokines and NFκB in Alzheimer’s disease." Doctoral thesis, Stockholm University, Department of Neurochemistry, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-990.
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Alzheimer’s disease is the most common form of dementia. It is a neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. The main constituent of the senile plaques is the neurotoxic β-amyloid peptide. Surrounding the senile plaques are activated astrocytes and microglia, believed to contribute to neurotoxicity through secretion of proinflammatory cytokines, like interleukin-1β and interleukin-6. For many inflammatory actions, including the cytokine induction in glial cells, the transcription factor NFκB plays a key role. This suggests that therapeutical strategies aimed to control the development of Alzheimer’s disease could include administration of drugs that hinder NFκB activation.
The major aim of this thesis was to examine the effects of β-amyloid together with interleukin-1β on cytokine expression as well as NFκB activation in glial cells. The possibility to block NFκB activation, and downstream effects like interleukin-6 expression, by using an NFκB decoy was investigated. The possibility to improve the cellular uptake of the decoy by linking it to a cell-penetrating peptide was also investigated.
The results obtained provide supportive evidence that inflammatory cytokines are induced by β-amyloid, and that they can indeed potentiate its effects. The results further demonstrate that by blocking NFκB activation, the induction of interleukin-6 expression can be inhibited. By using an improved cellular delivery system, the uptake of the NFκB decoy and hence the downstream cytokine inhibition could be increased. In conclusion, these results demonstrate the possibility to decrease the inflammatory reactions taken place in Alzheimer’s disease brains, which may ultimately lead to a possible way of controlling this disorder.
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Englund, Hillevi. "Soluble amyloid-β aggregates in Alzheimer’s disease." Doctoral thesis, Uppsala universitet, Institutionen för folkhälso- och vårdvetenskap, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-98512.
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Soluble oligomeric aggregates of the amyloid-β (Aβ) peptide are suggested to initiate Alzheimer's disease (AD), leading to impaired synapse signalling, widespread neuronal death and loss of cognitive functions. These aggregates seem tightly linked to disease progression, and have therefore gained much attention as potential novel disease markers. In this thesis soluble oligomeric Aβ aggregates in general, and the Aβ protofibril species in particular, have been investigated with the aim to quantify and determine their role in AD pathogenesis. Sandwich-ELISAs specifically measuring Aβ42 peptides are widely used both in AD research and as complements for clinical diagnosis. Here it was demonstrated that presence of soluble Aβ aggregates disturbs such analyses, making it difficult to interpret the results. This discovery was made through analyses of samples from cell- and mouse models carrying the AD causing 'Arctic' APP mutation. When analyzed by ELISA, Aβ42 levels were reduced in Arctic samples, in contrast to levels measured by denaturing SDS-PAGE Western blot. The same divergence in Aβ42-levels between analyses was observed in CSF samples from Down syndrome infants. The discrepancy between methods was hypothesized to be due to presence of soluble Aβ aggregates leading to impaired ELISA detection caused by epitope masking. This was confirmed by developing a protofibril specific ELISA, by which samples from Arctic cell- and mouse models were demonstrated to have enhanced Aβ protofibril levels. AD patients have reduced ELISA-measured Aβ42-levels in CSF compared to healthy controls. To test if this reduction was due to oligomeric Aβ species present in AD CSF, Aβ42-levels were analyzed under both denaturing and non-denaturing conditions. These two measures were combined and an Aβ42 oligomer ratio established. Higher ratios were found in AD patients than healthy controls, implying that Aβ oligomers are present in CSF during Alzheimer pathogenesis. The observations from AD patients and young Down syndrome individuals suggest that Aβ42 oligomer formation is an early mechanism of AD pathogenesis, which potentially could be used as a biomarker to monitor disease development.
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Tejera, Darío [Verfasser]. "Microglial Activation in Alzheimer’s Disease / Darío Tejera." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1189730685/34.
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Whiteley, Chris G. "Alzheimer’s disease: making sense of the stress." SM Online Publishers LLC, 2016. http://hdl.handle.net/10962/67072.
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publisher versionTo facilitate a deep understanding of the mechanisms involved in neurodegeneration and Alzheimer’s disease fundamental knowledge is required about the action and function of enzymes in the brain that not only metabolise arginine (neuronal nitric oxide synthase) but are closely associated with oxidative (superoxide dismutase; catalase; glutathione peroxidase) and/or nitrosative stress. In particular the focus extends towards enzymes that contribute to amyloid peptide aggregation and senile plaquedeposits (fibrillogenesis). Of special importance are the glycine zipper regions within these amyloid peptides, especially Aβ25-29 and Aβ29-33 (that contains two isoleucine residues) and the pentapeptide Aβ17-21 (that contains two phenylalanines), each generated by enzymatic cleavage of the intramembrane amyloid precursor protein. Use of antisense-sense technology has identified regions in each enzyme that are capable of binding with the amyloid peptides. After an initial inhibition of each enzyme there is an oligomerisation into soluble fibrils which accumulate and eventually precipitate. The use of nanoparticles do not just prevent but reverse the formation of these fibrils either by disrupting the binary adduct – enzyme-Aβ-peptide- or by reaction with, and therefore deplete, Aβ-monomers in solution and so block potential aggregation sites on the enzyme itself. Future therapy towards Alzheimer’s disease should target the C-terminal region of the amyloid precursor protein and substitute hydrophobic residues for the glycine amino acids within the glycine zipper region.
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GANDHI, RONAK. "“CLICKED” BIVALENT MULTIFUNCTIONAL LIGANDS IN ALZHEIMER’S DISEASE." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/225.
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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by beta-amyloid (Aβ) aggregation/oligomerization, biometal dyshomeostasis, oxidative stress, and neuroinflammation. The multifactorial nature of AD may indicate the therapeutic potential of multifunctional ligands that tackle various risk factors simultaneously as effective AD-modifying agents. This notion is further supported by the fact that while numerous AD-modifying agents targeting one single risk factor have been developed and a number of them entered clinical trials, none of them has been successfully approved by the FDA. Furthermore, neuronal cell membrane/lipid rafts (CM/LR) have been demonstrated to associate with all the indicated risk factors, indicating that this relationship can be exploited therapeutically to design strategically distinct multifunctional ligands by incorporating CM/LR anchorage into molecular design. With the long-term goal of developing multifunctional ligands to slow or stop the progression of AD, recently we have embarked on the development of bivalent multifunctional Aβ oligomerization inhibitors (BMOIs) as potential AD-modifying agents. These BMAOIs contain curcumin as the multifunctional moiety and cholesterol as the CM/LR anchorage moiety linked by a spacer to co-target AβOs, CM/LR, and oxidative stress. The hypothesis of the BMAOI strategy is that BMAOIs will anchor/target the multifunctional AβO inhibitor moiety inside, or in the vicinity of, CM/LR in which Aβ oligomerization, Aβ/biometal interaction and oxidative stress occur to efficiently interfere with these processes. In support of this hypothesis, proof-of-concept of the BMAOIs strategy has been reached through our preliminary studies. Our results demonstrated that: 1) BMAOIs containing curcumin as the multifunctional AβO inhibitor and cholesterol as CM/LR anchor primarily localize to CM/LR while curcumin does not; 2) BMAOIs with optimal spacer length efficiently inhibit the production of intracellular AβOs and protect MC65 cells from AβO-induced cell death (EC50~3 µM) while curcumin exhibits no significant activity; 3) these active BMAOIs retain curcumin’s antioxidant and metal complexation properties. Our preliminary studies also demonstrated the critical roles of spacer length and connectivity in the molecular design of BMAOIs and one lead compound was identified for further structural modification and optimization. Furthermore, this lead compound was shown to cross the blood-brain barrier (BBB) in a preliminary in vivo study as well as bind to Aβ plaques. Taken together, these results clearly reach the proof-of-concept of BMAOIs and confirm the rationale of designing BMAOIs to develop potential AD-modifying agents. In this thesis, we continued the exploration and validation of the BMAOI strategy by designing and biological characterizing a series of BMAOIs containing cholesterylamine as the CM/LR anchorage moiety and curcumin as the multifunctional moiety. Ten BMAOIs with the spacer length of 15, 17, 19, 21, and 23 atoms were designed and synthesized. Initially, these BMAOIs were tested for the neuroprotective activity against the AβO-induced cytotoxicity in human neuroblastoma MC65 cells. Then, Western blot analysis was performed for active BMAOIs to confirm the association of neuroprotection and suppression of AβOs. Furthermore, active BMAOIs were examined for antioxidant and metal complexation properties. Finally, Aβ plaque binding was examined using transgenic AD mice brain sections. Our results demonstrated that the same spacer length but different connectivity are preferred in this new series of BMAOIs for neuroprotective activity as that of the lead compound from cholesterol series. Moreover, the neuroprotection activity is closely associated with the inhibition of AβOs as demonstrated by Western blot analysis. In addition, the active BMAOIs retain the antioxidant and biometal binding properties of curcumin. More importantly, the binding affinity to the Aβ plaques was again confirmed for the new BMAOIs containing cholesterylamine. In summary, the design and characterization of the new series BMAOIs further confirmed the rationale of BMAOI strategy and their potential to lead to a new direction in development of effective AD-modifying and treatment agents.
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Smith, Simon. "Polyunsaturated fatty acid oxidation in Alzheimer’s disease." Thesis, Aston University, 2011. http://publications.aston.ac.uk/16499/.
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Alzheimer’s disease is a neurodegenerative disorder which has been characterised with genetic (apolipoproteins), protein (ß-amyloid and tau) and lipid oxidation/metabolism alterations in its pathogenesis. In conjunction with the Dementia Research Group, Bristol University, investigation into genetic, protein and lipid oxidation in Alzheimer’s disease was conducted. A large sample cohort using the double-blind criteria, along with various clinical and chemical data sets were used to improve the statistical analysis and therefore the strength of this particular study. Bristol University completed genetic and protein analysis with lipid oxidation assays performed at Aston University. Lipid oxidation is a complex process that creates various biomarkers, from transient intermediates, to short carbon chain products and cyclic ring structures. Quantification of these products was performed on lipid extracts of donated clinical diseased and non-diseased frontal and temporal brain regions, from the Brain Bank within Frenchay Hospital. The initial unoxidised fatty acids, first transient oxidation intermediates the conjugated dienes and lipid hydroperoxides, the endpoint aldehyde biomarkers and finally the cyclic isoprostanes and neuroprostanes were determined to investigate lipid oxidation in Alzheimer’s. Antioxidant levels were also investigated to observe the effect of oxidation on the defence pathways. Assays utilised in this analysis included; fatty acid composition by GC-FID, conjugated diene levels by HPLC-UV and UV-spec, lipid hydroperoxide levels by FOX, aldehyde content by TBARs, antioxidant status by TEAC and finally isoprostane and neuroprostane quantification using a newly developed EI-MS method. This method involved the SIM of specific ions from F-ring isoprostane and neuroprostane fragmentation, which enabled EI-MS to be used for their quantification. Analyses demonstrated that there was no significant difference between control and Alzheimer samples across all the oxidation biomarkers for both brain regions. Antioxidants were the only marker that showed a clear variance; with Alzheimer samples having higher levels than the age matched controls. This unique finding is supported with the observed lower levels of lipid oxidation biomarkers in Alzheimer brain region samples. The increased antioxidant levels indicate protection against oxidation which may be a host response to counteract the oxidative pathways, but this requires further investigation. In terms of lipid oxidation, no definitive markers or target site for therapeutic intervention have been revealed. This study concludes that dietary supplementation of omega-3 fatty acids or antioxidants would most likely be ineffective against Alzheimer disease, although it may support improvement in other areas of general health.