(422e) Development of Human iPSC-Derived Neuron Culture to Study the Contribution of Gene Environmental Interactions to the on-Set of Alzheimer’s Disease

Alzheimer’s Disease is an incurable and debilitating conditions that can result in progressive degeneration and death of nerve cells. Although there are lots of promising therapeutics that showed efficacy in rodent models, few translated into human drug targets potentially due to the significant difference between human and rodent nervous systems. Recent advances in stem cell technology has enabled development of 2D and 3D neuron culture system mimicking physiological composition, cell-cell interactions and their spatial distributions in human tissues. Furthermore CRISPR technology has enabled the development of novel engineered cell lines carrying homozygous mutations that have been validated to correlate with the onset of Alzheimer’s Disease. Here, we utilized CRISPR edited and patient derived human iPSCs to study the effects of gene environmental interactions in driving the establishment of AD phenotype. We specifically focused on PSEN2 mutations because they have been reported as the most common cause of familial Alzheimer’s Disease. During the course neuron differentiation, we added the environmental compounding effects by applying exposure of various neurotoxicants developmentally in early differentiation stage. We assessed changes in transcriptome and epigenome along with phenotypic changes driven by genetic and/or environmental effects. Time-course analysis was performed to continuously track the persistent neurotoxic effects among different genotypes. High-throughput imaging platform and modular analysis pipeline was established to systematically monitor epigenetic modifications caused by gene and environmental effects. Collectively our results can identify high-risk genotype and environmental exposures that contributes to the early onset of Alzheimer’s disease.