Study of PI3K protective actinos in Aß42-induced neurodegeneration

Resumen

In this thesis we aimed to evaluate the ability of PI3K overexpression to induce synaptogenesis in a pathological context where synapses are degenerated due to Aβ42 accumulation. In addition we analyzed the mechanism underlying PI3K actions in Aβ42 affected synapses, and the overall effects that synaptic changes have from a whole organism perspective. Our data demonstrated that PI3K activation is beneficial in Aβ42 neurodegeneration since it prevented synapse loss, microtubule dynamics defects, and locomotion and lifespan reduction. Furthermore, we described a novel effect of PI3K in Aβ aggregation that induces the generation of insoluble deposit. This change in conformation is suggested to occur due to a PI3K mediated phosphorylation in residue Ser-­‐26 of Aβ backbone. Synaptogenic and aggregation effects of PI3K in Aβ42 neurodegeneration are also reproduced in human neuroblastoma cells, proving that both actions are conserved in humans, and suggesting that it could be considered for future therapeutic studies in AD. In addition, discovery of a transient neuronal enhancer activation event in epithelial cells during early development in Drosophila, helped us uncover new Aβ42 toxic effects in non-­‐neuronal cells. In epithelial cells Aβ activated apoptosis and induced Wnt signaling misregulation. Both in epithelial cells and in neurosecretory cells Aβ42 deleterious effects were restored by PI3K.