The impact of Aβ on the Neurabin/PP1 complex

• Autor(a) principal: Alves, Helder Luís da Costa
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/15017
• topic: Biomedicina; Doença de Alzheimer; Neurobiologia molecular; Neurotransmissores; Proteínas

Our brain is a complex structure constituted by neurons capable of communicating through synapses, which generally occur between the axon terminal and the dendritic spine of two different neurons. These dendritic spines are dynamic, which allow for the rapid adaptation to the different stimuli they receive. PP1 is a phosphatase protein which catalyzes the majority of dephosphorylation reactions that occur in our body. It is involved in several different functions, from glycogen metabolism to synaptic regulation. Neurabins are two structurally and functionally similar proteins, highly concentrated in dendritic spines, where they interact with several proteins – PP1 included –, and target them to receptors, the cytoskeleton and to other cellular compartments. Thus, neurabins regulate neuronal morphology and synaptic transmission, and hence, synaptic plasticity. Alzheimer’s disease is the most common neurodegenerative disease and it is characterized by the deposition of Aβ and the presence of neurofibrilliary tangles, by the loss of synapses and neuronal death, and by the gradual loss of memory and other cognitive functions. APP is an integral membrane protein which, in Alzheimer’s disease, is abnormally cleaved via the amyloidogenic pathway, thus resulting in the overproduction of a toxic peptide, Aβ, believed to be the major culprit of the changes observed in this disease. The main aim of this thesis was to study the effects of Aβ on neurabins expression and to evaluate its effects on the neurabin/PP1 complex. The results here reported showed a slight decrease in both neurabins expression levels when Aβ was added to the cells, possibly due to the morphological changes and synaptic dysfunction this peptide induces. It was also here reported that Aβ interferes with the neurabin-1/PP1 complex. This may be related to the direct effect of Aβ on neurabin-1 or due to the imbalance of phosphatases and kinases seen when Aβ is added, which could result in a decrease of neurabin-1’s affinity for PP1. The same effect was not seen with the neurabin-2/PP1 complex, possibly because they are differently regulated by several kinases. The immunocytochemistry study here performed did not show any changes between the co-localization of neurabin-1 and PP1, and allowed for assessment of cellular distribution of neurabin-1 and neurabin-2 in SH-SY5Y cells. The experimental procedures here performed allowed us to conclude that Aβ interferes with the expression of both neurabins and with the interaction between neurabin-1 and PP1. However, additional studies need to be conducted in order to understand the physiological relevance of this complex.