Understanding neuronal dysfunction in Down Syndrome using assembloids and xenotransplanted cortical organoids

People with Down Syndrome (DS) have an intellectual disability and are more likely to develop Alzheimer’s Disease (AD) earlier than the general population because of the extra copy of chromosome twenty-one, affecting neuronal activity and connectivity. In this proposal, we are using a three-dimensional patient-derived human cellular model system of regionally-patterned cortical organoids to determine how trisomy 21 affects cellular, functional, and motility-related neuronal properties and the accumulation of pathological proteins. Furthermore, our studies will include organoid xenotransplantations into mouse cortex that provides a neuronal maturation- promoting environment and allows the assessment of how spontaneous and stimulus-induced neuronal function in implanted organoids is impacted in trisomy, which will contribute to our understanding of the mechanisms underlying intellectual deficits and AD pathology in DS.