Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming

Yamanaka factors (YFs) can reverse some aging features in mammalian tissues, but their effects on the brain remain largely unexplored. Here, we induced YFs in the mouse brain in a controlled spatio-temporal manner in two different scenarios: brain development, and adult stages in the context of neurodegeneration. Embryonic induction of YFs perturbed cell identity of both progenitors and neurons, but transient and low-level expression is tolerated by these cells during development. Under these conditions, YFs induction led to expanded neurogenesis, increased number of upper cortical neurons, and enhanced motor and social behavior of adult mice. Additionally, controlled YF induction is tolerated by principal neurons in the adult dorsal hippocampus and prevented the development of several hallmarks of Alzheimer’s disease, including cognitive decline and altered molecular signatures, in the 5xFAD mouse model. Overall, these results highlight the powerful impact of YFs on neurogenesis and their potential use in brain disorders. Highlights ### Competing Interest Statement M.S. is shareholder of Senolytic Therapeutics, Life Biosciences, Rejuveron Senescence Therapeutics and Altos Labs. M.S. was consultant until the end of 2022 of Rejuveron Senescence Therapeutics and Altos Labs. MA is shareholder of Altos Labs. All other authors declare no competing interests.