Abnormal protein phosphorylation in Alzheimer's disease

• Autor(a) principal: Oliveira, Joana Machado de
• Data de Publicação: 2011
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/7388
• topic: Biomedicina; Doença de Alzheimer; Proteínas; Fosforilação

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.