PI3K activation prevents Aβ42-induced synapse loss and favors insoluble amyloid deposits formation
Alzheimers disease is, to a large extent, a disease of the synapse triggered by the unbalanced amyloidogenic cleavage of the amyloid precursor protein APP. Excess of A{beta}42 peptide in particular is considered a hallmark of the disease. Here we drive the expression of the human A{beta}42 peptide to assay the neuroprotective effects of PI3K in adult Drosophila melanogaster. We show that the neuronal expression of the human peptide elicits progressive toxicity in the adult. The pathological traits include reduced axonal transport, synapse loss, defective climbing ability and olfactory perception, as well as life-span reduction. The A{beta}42-dependent synapse decay does not involve transcriptional changes in the core synaptic protein encoding genes: bruchpilot, liprin and synaptobrevin. All toxicity features, however, are suppressed by the co-expression of PI3K. Moreover, PI3K activation induces a significant increase of 6E10 and Thioflavin-positive amyloid deposits. Mechanistically, we suggest that A{beta}42-Ser26 could be a candidate residue for direct or indirect phosphorylation by PI3K. Finally, along with these in vivo experiments we further analyze A{beta}42 toxicity and its suppression by PI3K activation in in vitro assays with SH-SY5Y human neuroblastoma cell cultures, where A{beta}42 aggregation into large insoluble deposits is reproduced. Taken together, these results uncover a potential novel pharmacological strategy against this disease with PI3K activation as a target.