An integrative systems-biology approach defines mechanisms of Alzheimer’s disease neurodegeneration

Abstract Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimer’s disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila with human and Drosophila Alzheimer’s disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimer’s disease and identified Alzheimer’s disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimer’s disease multi-omic data. We computationally predicted and experimentally demonstrated how HNRNPA2B1 and MEPCE enhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimer’s disease.