Studying the role of human Amyloid precursor protein (APP) during human cortical neurogenesis

The neocortex is the highly elaborate part of the human brain which is responsible for complex cognitive behavior and which underwent significant expansion in the primate and then the human lineage during evolution. In part, this expansion is thought to be dependent on the capacity of human cortical progenitors to retain progeny identity for a long period of time while generating neurons, before ultimately differentiating. The Amyloid Precursor Protein (APP), which is responsible for genetic forms of Alzheimer disease, is highly expressed in early embryonic days in human telencephalic neurospheres, along with differentiation, migration and maturation of cortical neurons. However, the role of APP is human context development is completely unexplored. To assess APP role in human cortical development, we produced APP knock-out iPSC in two different genetic backgrounds. In summary, this project reveals a human context specific role for APP in regulating neurogenesis and identifies the regulation of cellular stress as a potential intrinsic mechanism for maintaining human cortical progenitor fate.