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I! Programa De Pós-Graduação Em Ciências Biológicas PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS BIOLÓGICAS: BIOQUÍMICA DEPARTAMENTO DE BIOQUÍMICA INSTITUTO DE CIÊNCIAS BÁSICAS DA SAÚDE UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL Tese de Doutorado O envolvimento da proteína fosfatase 2A e do sistema glutamatérgico em processos neurodegenerativos relacionados à doença de Alzheimer: mecanismos e biomarcadores de imagem Eduardo Rigon Zimmer Porto Alegre 2015 ! I!! PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS BIOLÓGICAS: BIOQUÍMICA DEPARTAMENTO DE BIOQUÍMICA INSTITUTO DE CIÊNCIAS BÁSICAS DA SAÚDE UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL O envolvimento da proteína fosfatase 2A e do sistema glutamatérgico em processos neurodegenerativos relacionados à doença de Alzheimer: mecanismos e biomarcadores de imagem Tese apresentada ao Programa de Pós- Graduação em Ciências Biológicas – Bioquímica da Universidade Federal do Rio Grande do Sul, como requisito parcial à obtenção do grau de Doutor em Bioquímica. Eduardo Rigon Zimmer Orientador: Prof. Luis Valmor Cruz Portela Porto Alegre 2015 ! II!! “We are all agreed that your theory is crazy. The question which divides us is whether it is crazy enough to have a chance of being correct.” Niels Bohr ! III! ! Aos meus pais, pelo ombro, pelo choro, pelo sorriso, pelo abraço e pelo suporte incondicional. ! IV! ! Agradecimentos Ao meu orientador, Professor Luis Valmor Cruz Portela, um grande pesquisador e amigo, por ter me iniciado na ciência e ser meu maior guia científico durante todos estes anos. Ao Professor Pedro Rosa-Neto, um grande neurocientista e amigo, pela orientação, liberdade científica e as discussões intermináveis. Ao Professor Diogo Onofre Gomes de Souza, o “Mestre”, por ser um exemplo de amor a vida e a pesquisa científica, sem dúvidas um dos meus maiores incentivadores nesta caminhada. Ao Professor Marcelo de Oliveira Dietrich, um pesquisador genial e amigo, por todos estes anos de orientação científica e de “normalidade”. Ao pessoal dos laboratórios 26 e 28 do Departamento de Bioquímica da UFRGS e do Translational Neuroimaging Laboratory da McGill, pela ajuda nos procedimentos científicos e por terem me ensinado muito sobre amizade. A Fabiana de Melo, minha vida, por ter me ensinado o significado do amor verdadeiro, e por ter sido minha maior companheira durante esta caminhada. Agradeço diariamente por fazeres parte de minha vida. Aos meus irmãos, Aline, Karine e Marcelo, grandes pesquisadores, pelo amor e apoio durante todos estes anos. Sem vocês eu nada seria. A minha mãe, Arlete, pelo amor incondicional, apoio constante e força nas horas difíceis. Tu és meu maior pilar. Ao meu Pai, Nelson, que teve o sonho de vida acadêmica interrompido, pelo apoio incondicional e por ter sido meu maior incentivador. Esta tese também és tua. ! V!! APRESENTAÇÃO Esta tese está organizada em três Partes, cada uma sendo constituída dos seguintes itens: Parte I: Resumo, Resumo em inglês (abstract), Lista de abreviações, Introdução e Objetivos; Parte II: Resultados, que estão divididos em capítulos, sendo cada que capítulo contém um breve prefácio seguido de um artigo científico; Parte III: Discussão, Conclusão, anexos e Referências bibliográficas citadas na Introdução da Parte I e Discussão da Parte III. Na seção “anexos” estão os artigos científicos que foram realizados durante o período de doutoramento que tem conteúdo associado a tema da tese (Anexo I) e que não são diretamente associados com o tema da tese (Anexo II). Os trabalhos elaborados nesta tese foram desenvolvidos no laboratório de Neurotrauma, no Departamento de Bioquímica da Universidade Federal do Rio Grande do Sul (UFRGS), sob a orientação do Dr. Luis Valmor Cruz Portela, como também no Laboratório de Neuroimagem translacional da Universidade McGill (Canada), sob a orientação do Dr. Pedro Rosa- Neto. ! VI! ! Sumário APRESENTAÇÃO!..................................................................................................................!VI! PARTE I!......................................................................................................................................!1! Resumo!.................................................................................................................................................!2! Abstract!........................................................................................................................................!3! Introdução!...................................................................................................................................!7! A!doença!de!Alzheimer!...................................................................................................................!8! Mecanismos!envolvidos!na!doença!de!Alzheimer!...............................................................!10! A!deposição!de!β.amilóide!.......................................................................................................................!10! A!proteína!tau!................................................................................................................................................!12! Neuroinflamação!..........................................................................................................................................!14! Neurotransmissão!glutamatérgica!.......................................................................................................!15! Biomarcadores!................................................................................................................................!17! Biomarcadores!de!β.Amilóide!................................................................................................................!19! Biomarcadores!de!Neurodegeneração!................................................................................................!21! Outros!biomarcadores!...............................................................................................................................!23! Modelos!hipotéticos!de!biomarcadores!.............................................................................................!24! Objetivo!..............................................................................................................................................!25! ObJetivos!específicos!..................................................................................................................................!25! PARTE II!..................................................................................................................................!27! Capítulo!I.!Inhibition(of(Protein(phosphatase(2A(links(tau(phosphorylation,(oxidative(stress( and(memory(decline!..........................................................................................................................!28! Capítulo!II.!Pretreatment(with(Memantine(Prevents(Alzheimer?Like(Alterations(Induced(by( Intrahippocampal(Okadaic(Acid(Administration(in(Rats.!...........................................................!55! Capítulo!III.!Inhibition(of(protein(phosphatase(2A:(focus(on(the(glutamatergic(system.!.....!65! Capítulo!IV.!Long?term(NMDAR(antagonism(correlates(reduced(astrocytic(glutamate( uptake(with(anxiety?like(phenotype.!...............................................................................................!69! Capítulo!V.!Imaging(biomarkers(for(amyloid:(a(new(generation(of(probes(and(what(lies( ahead.!...................................................................................................................................................!78! Capítulo!VI.!Use(of(amyloid(PET(across(the(spectrum(of(Alzheimer’s(disease:(clinical(utility( and(associated(ethical(issues.!...........................................................................................................!84! Capítulo!VII.!Amyloid(imaging(in(Alzheimer’s(disease:(a(potential(new(era(of(personalized( medicine?!.............................................................................................................................................!91! Capítulo!VIII.!Developments(in(Tau(PET(Imaging.!.....................................................................!98! Capítulo!X.!MicroPET(imaging(and(transgenic(models:(a(blueprint(for(Alzheimer's(disease( clinical(research.!.............................................................................................................................!120! Capítulo!XI.!In(vivo(tracking(of(tau(pathology(using(positron(emission(tomography((PET)( molecular(imaging(in(small(animals.!...........................................................................................!136! Capítulo!XII.!Imaging(in(vivo(glutamate(fluctuations(with([11C]ABP688:(a(GLT?1(challenge( with(ceftriaxone.!..............................................................................................................................!143! Capítulo!XIII.![18F]FDG(PET(signal(is(driven(by(astroglial(glutamate(transport.!...............!150! PARTE III!..............................................................................................................................!151! Discussão!.................................................................................................................................!152! Conclusão!...............................................................................................................................!170! Referências!.............................................................................................................................!172! ! VII! ! Anexos!...........................................................................................................................................!i!
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