Amyloid precursor protein dosage normalization rescues neurogenesis and Alzheimer's Disease phenotypes associated with Down Syndrome.

Down Syndrome (DS) is the most abundant genetic form of mental retardation. It is caused by the triplication of partial or complete human chromosome 21 (HSA21). The molecular mechanisms of DS are not fully understood. Amyloid precursor protein (APP) resides on HSA21 and is triplicated in DS. While it is not thought to be a part of the "Down syndrome Critical Region", APP plays a role in developmental and post-natal neurogenesis and synaptic plasticity, thus, its triplication may affect cortical development in DS. Further, mutations in APP cause familial Alzheimer's disease (AD). However, whether APP overdose is sufficient or required for the development of Alzheimer's disease in DS is not fully elucidated. Here, we addressed the role of APP overdose in neuronal development and AD pathology. Using DS patient-derived induced pluripotent stem cells in which one copy of APP was silenced using CRISPR-Cas9, we examined developmenta neurogenesis, AD-related pathology and the expression levels of genes on HSA21 that are implicated in DS, neurodegeneration and inflammation. Amyloid precursor protein triplication, in DS induced pluripotent stem cells, led to reduced stem cell proliferation, enhanced differentiation into neurons, increased amyloid pathology, and altered protein levels of selected genes on HSA21. Correction of APP gene dosage rescued the altered neurogenesis phenotype and reduced pathological amyloidogenic processing. These data highlight APP dosage as a key regulator of neuronal maturation and AD pathology in DS, suggesting therapeutic value in targeting APP expression to mitigate neurodevelopmental and neurodegenerative features of the disorder.