The relevence of insulin signalling in Alzheimer's disease

• Autor(a) principal: Alves, Steven Ribeiro
• Data de Publicação: 2017
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/22020
• topic: Doença de Alzheimer; Resistência à insulina; Fosforilação

Alzheimer’s disease (AD) is the most common type of dementia worldwide. It is molecularly characterized by deposition of extracellular senile plaques (SPs) composed by aggregated amyloid beta (Aβ) peptide, the formation of neurofibrillary tangles (NFTs) derived from hyperphosphorylation of the microtubule-associated protein Tau, synaptic dysfunction due to the deposits of SPs and NFTs and oxidative stress induced by impaired metabolic pathways. The insulin signalling pathway can play a major role in diverse AD related pathways, such as APP cleavage, Tau hyperphosphorylation, Apolipoprotein E (ApoE) influence in insulin signalling efficiency and the insulin degrading enzyme, which is also the major Aβ degrading enzyme. Growing evidence links AD with type 2 diabetes (T2D) due to impaired insulin signalling (IS) and brain insulin resistance. In a cohort based study in the Aveiro region, a correlation between diabetes and poor cognitive scores in the Mini Mental State Examination (MMSE) test were observed, with a p-value of 0.072. Additionally, carriers of the allele ApoE-ɛ2 appeared to be protective against diabetes, in the literature the same allele appears to be protective for AD. Posteriorly, the analysis of protein interactions, via the development of interactome networks, identified several proteins involved in both AD and the IS pathways. Also, by correlating these pathways with the synapse proteome, a very high overlap was observed (88% for AD, 79% for IS and 96% for AD and IS coincident proteins), enforcing the importance of both pathways in synaptic signalling and plasticity. From gene ontology studies, it was possible to assess the principal biological processes and molecular functions of the dataset of proteins. For AD, response to stimulus, cellular component organization, cell communication, signalling, protein binding, receptor binding and kinase binding were categories with elevated representation. Regarding coincident proteins between AD and IS pathways, an increase in all categories was observed, meaning that insulin plays a pivotal role in many AD events. Finally, the analysis of SH-SY5Y differentiated cells treated with 0, 1, 10 and 100 nM of insulin for 0, 10 and 60 minutes, showed a decrease on the intracellular total levels of protein Tau and an increase in the phosphorylation at serine 396. Regarding the amyloid precursor protein (APP), increases in intracellular levels were observed, when treated with insulin for 10 minutes, followed by a decrease for 60 minutes exposure. The phosphorylation of APP at threonine 668, has previously been related to increased production of Aβ, by promoting APP cleavage via the amyloidogenic pathway. In cells treated with insulin, a clear increase was detected at the 10-minute time point. At 60 minutes, the levels of phosphorylation were low probably due to low total APP levels.