The Amyloid Precursor Protein regulates human cortical neurogenesis

The human neocortex has undergone significant expansion during evolution partially underlying increased human cognitive capacities. The 16 billion neurons of the human neocortex are derived from a limited number of cortical neural progenitor cells (NPCs). Human cortical NPCs initially generate neurons at a slow rate while preserving their progenitor state for a prolonged period, partly contributing to increased human cortical size. How the balance between the progenitor state and neurogenic state is regulated, and whether it contributes to species-specific brain patterning, is poorly understood. We find that the human Amyloid Precursor Protein (APP), whose mutations cause Alzheimer’s disease, specifically regulates this fine balance. Mechanistically, APP regulates these two aspects via two pathways: the AP1 transcription factor and the canonical Wnt pathway. We propose that APP is a homeostatic regulator of the neurogenic potential of cortical NPCs thus potentially contributing to human-specific patterns of neurogenesis.