The amyloid-β protein precursor (AβPP) is subjected to sequential intramembrane proteolysis by α-, β-, andγ-secretases, producing secreted amyloid-β (Aβ) peptides and a cytoplasmically released AβPP Intracellular Domain (AICD). AICD complexes with transcription factors in the nucleus, suggesting that this AβPP fragment serves as an active signaling effector that regulates downstream genes, although its nuclear targets are poorly defined. To further understand this potential signaling mechanism mediated by AβPP, we performed a transcriptomic identification of the Drosophila genome that is regulated by the fly AβPP orthologue in fly mushroom body neurons, which control learning- and memory-based behaviors. We find significant changes in expression of 245 genes, representing approximately 1.6% of the Drosophila genome, with the changes ranging from +6 fold to -40 fold. The largest class of responsive targets corresponds to non-protein coding genes and includes microRNAs that have been previously implicated in Alzheimer's disease pathophysiology. Several genes were identified in our Drosophila microarray analyses that have also emerged as putative AβPP targets in similar mammalian transcriptomic studies. Our results also indicate a role for AβPP in cellular pathways involving the regulation of Drosophila Casein Kinase II, mitochondrial oxidative phosphorylation, RNA processing, and innate immunity. Our findings provide insights into the intracellular events that are regulated by AβPP activity in healthy neurons and that might become dysregulated as a result of abnormal AβPP proteolysis in AD.
Keywords: APPL; Alzheimer’s disease; AβPP; Drosophila; amyloid-β protein precursor; microarray; mushroom body; transcriptional regulation.