Thesis (M.S.)--University of Michigan, 1996. / Includes bibliographical references.

Source: Masters Abstracts International, Volume: 46-05, page: 2668. Adviser: Wenyaw Chan. Includes bibliographical references.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 145-219.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Thesis (M.S.)--University of Michigan, [2000] / Includes bibliographical references.

Thesis (M.S.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Not Embargoed. Vita. Bibliography: 87-100.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.

The misfolding and aggregation of the beta cell hormone islet amyloid polypeptide (IAPP) into amyloid fibrils is the main pathological finding in islets of Langerhans in type 2 diabetes. Pathological assemblies of IAPP are cytotoxic and believed to contribute to the loss of insulin-producing beta cells. Changes in the microenvironment that could trigger the aggregation of IAPP are largely unknown. So is the possibility that islet amyloid can spread within or between tissues. The present thesis have explored the roles of glycosaminoglycan heparan sulfate (HS) and the novel anti-amyloid chaperone Bri2 BRICHOS domain in the assembly of IAPP amyloid and cytotoxic IAPP aggregates. Furthermore, cross-seeding as a molecular interaction between the observed connection of type 2 diabetes and Alzheimer disease has been examined. The N-terminal region of IAPP was required for binding to HS structures and induction of binding promoted amyloid formation. Interference in the HS-IAPP interaction by heparanase degradation of HS or by introducing short, soluble HS-structure fragments reduced amyloid deposition in cultured islets. Cytotoxicity induced by extracellular, aggregating IAPP was mediated via interactions with cell-surface HS. This suggests that HS plays an important role in islet amyloid deposition and associated toxicity. BRICHOS domain containing protein Bri2 was highly expressed in human beta cells and colocalized with IAPP intracellularly and in islet amyloid deposits. The BRICHOS domain effectively attenuated both IAPP amyloid formation and IAPP-induced cytotoxicity. These results propose Bri2 BRICHOS as a novel chaperone preventing IAPP aggregation in beta cells. The intravenous injection of IAPP, proIAPP or amyloid-β (Aβ) fibrils enhanced islet amyloidosis in transgenic human IAPP mice, demonstrating that both homologous- and heterologous seeding of islet amyloid can occur in vivo. IAPP colocalized with Aβ in brain amyloid from AD patients, and AD patients diagnosed with T2D displayed increased proportions of neuritic plaques, the more pathogenic plaque subtype. In conclusion, both IAPP amyloid formation and the cytotoxic effects of IAPP is dependent on interactions with HS whereas interactions with Bri2 BRICHOS is protective. Cross-seeding between Aβ and IAPP can occur in vivo and the two peptides colocalize in brain amyloid in AD patients.

Submitted by SANDRA LUCIA PETRILLO (sandrapetrillo.longlife@gmail.com) on 2017-12-11T17:56:53Z No. of bitstreams: 1 Dissertação_Mestrado_Sandra_Petrillo.pdf: 5408729 bytes, checksum: 260301e7ac6761c455f3e28f08f23ac3 (MD5) / Submitted by SANDRA LUCIA PETRILLO (sandrapetrillo.longlife@gmail.com) on 2017-12-11T18:47:11Z No. of bitstreams: 1 Dissertação_Mestrado_Sandra_Petrillo.pdf: 5408729 bytes, checksum: 260301e7ac6761c455f3e28f08f23ac3 (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2017-12-12T16:04:58Z (GMT) No. of bitstreams: 1 petrillo_sl_me_bot.pdf: 5408729 bytes, checksum: 260301e7ac6761c455f3e28f08f23ac3 (MD5) / Made available in DSpace on 2017-12-12T16:04:58Z (GMT). No. of bitstreams: 1 petrillo_sl_me_bot.pdf: 5408729 bytes, checksum: 260301e7ac6761c455f3e28f08f23ac3 (MD5) Previous issue date: 2017-07-14 / Objetivo: Avaliar desempenho do teste de rastreio Memory Impairment Screen (MIS) para a triagem diagnóstica da Demência na Doença de Alzheimer (DDA). Casuística e método: Estudo de acurácia realizado no Ambulatório de Geriatria do Centro de Saúde Escola da Faculdade de Medicina de Botucatu – Unesp. Casuística de 126 pacientes idosos, sendo aplicado o teste de avaliação cognitiva MIS, utilizando-se como padrão ouro os critérios diagnósticos da DDA propostos por Frota. O valor diagnóstico foi analisado pelo cálculo da sensibilidade, especificidade, valores preditivos (positivo e negativo) e razão de verossimilhança positiva e negativa. A curva ROC foi traçada para contribuir na avaliação do desempenho do MIS no diagnóstico da DDA. Resultados: Foram avaliados 126 idosos com média de idade de 71,6 + 7,8 anos, maioria do sexo feminino (65,9%) e com 1 a 4 anos de estudo (40%). A presença do diagnóstico de Doença de Alzheimer foi observada em 18 (14,3%) dos idosos avaliados. O teste de rastreio cognitivo pelo MIS apresentou valor de sensibilidade de 72,2%, especificidade de 83,3%, valor preditivo positivo de 41,9% e negativo de 94,7% e razões de verossimilhanças positiva de 433 e negativa de 33,3. A área sob a curva ROC foi de 0,78 (IC 95%, 0,65-0,9). Conclusão: O presente estudo evidenciou a aplicabilidade do teste MIS e sua eficácia no diagnóstico das alterações cognitivas em pacientes idosos, com valores significativos de sensibilidade e especificidade; apresentou vantagens de rapidez, fácil aplicabilidade e interpretação; independente de cultura, linguagem e escolaridade. O MIS oferece vantagens importantes como teste de rastreio para uso em cuidados primários a saúde, sendo necessário estudos complementares que possam indicar o uso isolado deste teste para exclusão de demência. / Objective: To evaluate the performance of the Memory Impairment Screen (MIS) for the diagnostic screening of Dementia in Alzheimer's Disease (AD). Methods: Accuracy study performed at the Geriatrics Outpatient Clinic of the School Health Center of Botucatu Medical School - Unesp. A total of 126 elderly patients were enrolled, and the MIS cognitive evaluation test was applied, using the AD diagnostic criteria proposed by Frota as the gold standard. The diagnostic value was analyzed by the calculation of sensitivity, specificity, predictive values (positive and negative) and positive and negative likelihood ratio. The ROC curve was drawn to contribute to the evaluation of MIS performance in the diagnosis of AD. Results: A total of 126 elderly individuals with a mean age of 71.6 ± 7.8 years, most of them female (65.9%) and 1 to 4 years of education (40%) were evaluated. The presence of the diagnosis of Alzheimer's disease was observed in 18 (14.3%) of the elderly evaluated. The MIS cognitive screening test showed a sensitivity of 72.2%, specificity of 83.3%, positive predictive value of 41.9% and negative of 94.7% and likelihood ratio of 433 and negative of 33,3. The area under the ROC curve was 0,78 (95% CI, 0.65-0.9). Conclusion: The present study evidenced the applicability of the MIS test and its efficacy in the diagnosis of cognitive alterations in elderly patients, with significant values of sensitivity and specificity; Presented advantages of speed, easy applicability and interpretation; Independent of culture, language and schooling. MIS offers important advantages as a screening test for use in primary health care, and further studies are needed to indicate the use of this test alone to exclude dementia.

[pt] A doença de Alzheimer é uma patologia multifatorial que, nos dias atuais, re-presenta a forma mais conhecida de demência em idosos. Baseado na hipótese me-tálica, pesquisas demonstraram que a interação de certos íons metálicos endógenos, como o Fe3+ e o Cu2+, com o peptídeo A beta provoca uma aceleração da formação de espécies oligoméricas e ainda contribui para o aumento do estresse oxidativo. Neste ínterim, a proposição de MPACs (do inglês, Metal-Protein Attenuating Coum-pounds, compostos atenuadores da interação metal-proteína) é uma abordagem pro-missora para evitar o progresso da demência, pois estas moléculas apresentam afi-nidade moderada por íons metálicos. Neste trabalho, sintetizaram-se três potencias MPACs hidrazônicos, INHOVA, 2PCAFUR e FUROVA e um complexo inédito de vanádio(IV), [VO(INHOVA)2(OH2)]·2HCl 1/2 MeOH (1), proposto como mo-delo de veículo para esses compostos. A caracterização destas moléculas foi possí-vel a partir de diferentes técnicas, como espectroscopia vibracional na região do infravermelho (IV), análise elementar (CHN), ressonância magnética nuclear de 1H (RMN de 1H), difração de raios-X em monocristal, ressonância paramagnética ele-trônica (EPR) e análise termogravimétrica (TGA). Os ligantes hidrazônicos não co-ordenados são suscetíveis à hidrólise, conforme estudado por espectroscopia de ab-sorção no UV-Vis. O complexo de vanádio (1), por outro lado, apresenta maior estabilidade, podendo atuar como veículo para esses e outros MPACs, preservando a integridade do ligante em solução. Neste contexto, complexos metálicos de vanádio tendo como ligantes INHOVA, 2PCAFUR e FUROVA se apresentam como bons candidatos a estudos mais aprofundados, a fim de avaliar sua viabilidade como possíveis carreadores de MPACs no tratamento da doença de Alzheimer. / [en] Alzheimer s disease is a multifactorial pathology that, currently, represents the most known form of dementia in the elderly. Based on the metal hypothesis, studies have shown that the interaction of certain endogenous metal ions, such as Fe3 plus and Cu2 plus, with the A beta peptide accelerates the formation of oligomeric species and also contributes to the increase of oxidative stress. In this context, the proposition of MPACs (Metal-Protein Attenuating Compounds) is a promising approach to prevent the progression of dementia because these molecules exhibit moderate affinity for metal ions. In this work, three potential hydrazonic MPACs were syn-thesized, INHOVA, 2PCAFUR and FUROVA and a novel vanadium(IV) complex, [VO(INHOVA)2(OH2)] 2HCl.1/2MeOH (1), proposed as vehicle model for these compounds. The characterization of these molecules was possible from different techniques such as vibrational spectroscopy in the infrared (IR) region, elemental analysis (CHN), proton nuclear magnetic resonance (1H-NMR), X-ray diffraction in monocristal, electronic paramagnetic resonance (EPR) and thermogravimetric analysis (TGA). Uncoordinated hydrazonic ligands are susceptible to hydrolysis as studied by UV-Vis absorption spectroscopy. The vanadium complex (1), on the other hand, present greater stability, being able to act as vehicle for this and other MPACs, preserving their integrity in solution. In this context, vanadium metal com-plexes containing INHOVA, 2PCAFUR and FUROVA as ligands present them-selves as good candidates for further studies in order to evaluate their viability as possible drugs for the treatment of Alzheimer s disease.