Manipulation of the APP levels using CRISPR/Cas9-based technologies in a Down syndrome iPS-based in vitro neurogenesis model reveals its substantial contribution to Alzheimer disease-like neuropathology.
Abstract: Early-onset Alzheimer’s disease-like pathology in Down syndrome is commonly attributed to an increased dosage of the amyloid precursor protein (APP) gene. To test this in an isogenic human model we deleted the supernumerary copy of the APP gene in trisomic DS iPSCs, or upregulated APP expression in euploid human pluripotent stem cells using CRISPRa. Cortical neuronal differentiation shows that an increased APP gene dosage is responsible for increased beta-amyloid production, altered Ab42/40 ratio and deposition of the pyroglutamate (E3)-containing amyloid aggregates, but not for several tau-related AD phenotypes or increased apoptosis. Transcriptome comparisons demonstrate that APP has a widespread and temporally-modulated impact on neuronal gene expression. Collectively, these data reveal an important role for APP in the amyloidogenic aspects of Alzheimer’s disease, but challenges the idea that increased APP levels are solely responsible for increasing specific phosphorylated forms of tau, or enhanced neuronal cell death in Down syndrome-associated AD-pathogenesis.