Abnormal protein phosphorylation in Alzheimer's disease

Joana Machado de

Oliveira

Fosforilação anormal de proteínas na Doença de

Alzheimer

Abnormal protein phosphorylation in Alzheimer’s

disease

Joana Machado de

Oliveira

Fosforilação anormal de proteínas na Doença de

Alzheimer

Abnormal protein phosphorylation in Alzheimer’s

disease

Dissertação apresentada à Universidade de Aveiro para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Biomedicina Molecular, realizada sob a orientação científica da Professora Doutora Ana Gabriela Henriques, Professora Auxiliar Convidada da Secção Autónoma de Ciências da Saúde da Universidade de Aveiro e co-orientação da Professora Doutora Odete da Cruz e Silva, Professora Auxiliar da Secção Autónoma de Ciências da Saúde da Universidade de Aveiro.

Esta dissertação contou com o apoio financeiro da FCT

(PTDC/QUIBIQ/101317/2008) e do Centro de Biologia Celular (CBC), Universidade de Aveiro.

Pelo amor incondicional, carinho, força e apoio, esta dissertação é dedicada aos meus pais, David e Glória, maninha e aos meus pequenos grandes amores, João e Beatriz.

o júri

presidente Professora Doutora Alcione Leite da Silva

Professora Associada Convidada da Secção Autónoma de Ciências da Saúde

Professora Doutora Ana Gabriela da Silva Cavaleiro Henriques

Professora Auxiliar Convidada da Secção Autónoma de Ciências da Saúde, Universidade de Aveiro

Professora Doutora Odete Abreu Beirão da Cruz e Silva

Professora Auxiliar com Agregação da Secção Autónoma de Ciências da Saúde, Universidade de Aveiro

Professora Virgínia Maria Dinis Carvalhais

agradecimentos Um agradecimento muito especial à Professora Doutora Ana Gabriela Henriques pela sua orientação, apoio, dedicação e encorajamento durante a realização desta dissertação. Obrigada por permitir o meu enriquecimento científico e profissional. Um agradecimento especial ao André, Inês e Diana que tão bem me acolheram na recta final desta dissertação.

À Professora Doutora Odete da Cruz e Silva pela oportunidade de participar neste projecto e por todo o apoio.

À Professora Doutora Sandra Rebelo pela sua disponibilidade

A todos os colegas do Laboratório de Neurociências, Sinalização Celular, Biogénese de Organelos e Investigação Clínica do Centro de Biologia Celular.

Aos investigadores do Centro de Biologia celular pelo apoio científico sem o qual o sucesso deste trabalho não seria possível.

Ao CBC, Universidade de Aveiro (UA), por todos os equipamentos e reagentes de base.

À FCT pelo financiamento do projecto PTDC/QUIBIQ/101317/2008.

Um agradecimento especial à Joana Rocha e Filipa Martins, colegas de laboratório mas, acima de tudo amigas, por todo o apoio e companheirismo. Obrigada Sarinha e Mariana.

A todos os meus amigos, obrigada pela vossa amizade.

Aos meus pais pelo amor, apoio e coragem que sempre me transmitiram e sem os quais este trabalho não seria possível.

A minha irmã e amiga, Severina, obrigada pelo amor, motivação e por ser, em parte, responsável por quem sou hoje. Ao Alfredo pelos conselhos e boa disposição.

Ao João e à Beatriz por alegrarem os meus dias!

Ao Joaquim Mário, pelo amor e carinho. Obrigada pela paciência e compreensão

palavras-chave Doença de Alzheimer, proteína precursora da amilóide, Abeta, fosforilação de proteínas

resumo A Doença de Alzheimer é uma patologia neurodegenerativa caracterizada pela presença de placas senis, emaranhados neurofibrilhares e perda sináptica. Aβ, o principal componente das placas senis, tem um papel fundamental na patologia, uma vez que, o aumento da sua produção e agregação está associada a neurotoxicidade, activação da resposta inflamatória e cascatas apoptóticas. Estes processos estão associados à morte neuronal, neurodegeneração e, consequentemente, com o declínio cognitivo gradual. Considera-se também alterações em vias de sinalização celular como um dos aspectos fundamentais da patologia. A fosforilação de proteínas é reconhecida como um mecanismo fundamental capaz de regular eventos intracelulares. Vários estudos têm descrito uma actividade anormal de proteínas cinases e fosfatases em cérebros de doentes, bem como níveis anormais de fosforilação da PPA (Proteína Precursora de Amilóide de Alzheimer), Tau, entre outras proteínas. A fosforilação é um dos mecanismos que regula as funções e processamento da PPA sendo esta uma proteína fosfo-específica descrita como hiperfosforilada nos cérebros de doentes de Alzheimer.

Devido à importância do Aβ e aos níveis de fosforilação anormal descritos na DA, os objectivos deste estudo eram a análise dos efeitos do Aβ na

fosforilação da PPA, em específico nos resíduos Thr668 e Tyr682, bem como nos níveis de fosforilação geral. Neste trabalho observaram-se níveis

aumentados de fosforilação nos resíduos especificados após a exposição ao Aβ sugerindo que este possa estar relacionado com a fosforilação anormal da PPA e, consequentemente, com o processamento desta. O trabalho

desenvolvido sugere ainda o envolvimento da proteína fosfatase 1 na

desfosforilação da PPA no resíduo Thr668. Adicionalmente, tanto o Aβ como a fosforilação no resíduo Thr668 regulam as interacções da PPA. Análise do fosfoproteoma revelou alterações em resposta ao tratamento com Aβ, estando proteínas envolvidas na transcrição de genes, cinases e fosfatases,

aumentadas após o tratamento com Aβ. Todos estes resultados sugerem que o Aβ pode estar relacionado com a fosforilação anormal de proteínas

conduzindo a uma sinalização intracelular anormal e consequentemente, contribuindo para a DA.

keywords Alzheimer´s disease, amyloid precursor protein, Abeta, protein phosphorylation

abstract AD is a neurodegenerative disorder neuropathologically characterized by the presence of senile plaques, neurofibrillary tangles and synaptic loss. The Aβ peptide, the major constituent of senile plaques, is a key player in AD pathology since increased Aβ production and aggregation was associated with neurotoxicity, activation of inflammatory response, and apoptotic cascades. These processes are associated with neuronal death, neurodegeneration and consequently gradual cognitive decline. Altered signal transduction is also thought to be one of the key aspects in AD pathology. Protein phosphorylation is recognized as a fundamental mechanism by which the regulation of key intracellular events is achieved. Several studies have reported abnormal protein kinase and protein phosphatase activities in AD brains as well as abnormal phosphorylation levels of APP and Tau proteins. Further, phosphorylation is one of the mechanisms that regulates APP function and processing. APP is a phospho-specific protein also described as being hyperphosphorylated in AD brains.

Due to the key role played by A and abnormal phosphorylation in AD pathology, the aim of this study was to analyze de Aβ effects on APP phosphorylation at Thr668 and Tyr682 as well on protein phosphorylation in general. In this work we could observe an increase in the phosphorylation level of APP at these specific residues upon Aβ exposure at low concentrations. The phosphatase involved in dephosphorylating the above mentioned residue (Thr668) was found to be protein phosphatase 1. Additionally, it was also observed that both Aβ and APP phosphorylation at Thr668 can regulate APP interactions. The phosphoproteome was in fact altered in response to Aβ exposure, and it was shown that proteins involved in fundamental cellular processes such as gene transcription and intracellular levels of protein kinases and phosphatases are increased upon Aβ treatment. Taken together these findings suggest that Aβ plays a role in abnormal protein phosphorylation, potentially leading to abnormal signaling cascades, and consequently contributing to AD pathology.







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