Modelling APOE ϵ3/4 allele-associated sporadic Alzheimer's disease in an induced neuron

The recent generation of induced neurons by direct lineage conversion holds promise for in vitro modelling of sporadic Alzheimer's disease. Here, we report the generation of induced neuron-based model of sporadic Alzheimer's disease in mice and humans, and used this system to explore the pathogenic mechanisms resulting from the sporadic Alzheimer's disease risk factor apolipoprotein E (APOE) ϵ3/4 allele. We show that mouse and human induced neurons overexpressing mutant amyloid precursor protein in the background of APOE ϵ3/4 allele exhibit altered amyloid precursor protein (APP) processing, abnormally increased production of amyloid-β 42 and hyperphosphorylation of tau. Importantly, we demonstrate that APOE ϵ3/4 patient induced neuron culture models can faithfully recapitulate molecular signatures seen in APOE ϵ3/4-associated sporadic Alzheimer's disease patients. Moreover, analysis of the gene network derived from APOE ϵ3/4 patient induced neurons reveals a strong interaction between APOE ϵ3/4 and another Alzheimer's disease risk factor, desmoglein 2 (DSG2). Knockdown of DSG2 in APOE ϵ3/4 induced neurons effectively rescued defective APP processing, demonstrating the functional importance of this interaction. These data provide a direct connection between APOE ϵ3/4 and another Alzheimer's disease susceptibility gene and demonstrate in proof of principle the utility of induced neuron-based modelling of Alzheimer's disease for therapeutic discovery.