The Role of Amyloid Precursor Protein in Deficits in Corticogenesis in Down Syndrome

Down Syndrome (DS) due to trisomy 21 results in significant developmental cortical malformation and invariably accumulation of Alzheimer’s Disease (AD) pathology with aging. Approximately fifty percent of people with DS will develop clinical AD. It is theorized that deficits in corticogenesis lead to abnormal neuronal networks vulnerable to the early, pervasive AD pathology observed in DS. Amyloid Precursor Protein (APP) is located on human chromosome 21 (HSA21) and overexpressed in DS tissues. Overexpression and increased metabolism of APP is thought to underlie these deficits given its well established role in molecular mechanisms of cortical development and AD. However, given the hundreds of genes located on HSA21, it remains to be established if normalization of APP gene copy number would be sufficient to rescue DS phenotypes. To that end, CRISPR-Cas9 technology was utilized to eliminate one copy of APP from human DS patient derived induced pluripotent stem cells (DS APP +/+/-) to address the hypothesis that increased APP gene dosage disrupts corticogenesis and promotes neuronal network vulnerability and AD pathology accumulation in DS cortical organoids. Isogenic control, DS, mock CRISPR-Cas9 DS, and DS APP +/+/- induced pluripotent stem cell lines were differentiated into dorsal forebrain organoids for characterization of corticogenesis and AD pathology. APP gene copy number contributed to decreased expression of neurogenic proteins, deficits in neuronal differentiation, and increased secretion of Aβ in DS cortical organoids. Taken together, this suggests that increased APP gene copy number dysregulates corticogenesis and promotes AD pathology in DS.