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

• Published in: Cell stem cell
• Main Authors: Shen, Yi-Ru, Zaballa, Sofia, Bech, Xavier, Sancho-Balsells, Anna, Rodríguez-Navarro, Irene, Cifuentes-Díaz, Carmen, Seyit-Bremer, Gönül, Chun, Seung Hee, Straub, Tobias, Abante, Jordi, Merino-Valverde, Iñaki, Richart, Laia, Gupta, Vipul, Li, Hao-Yi, Ballasch, Ivan, Alcázar, Noelia, Alberch, Jordi, Canals, Josep M., Abad, Maria, Serrano, Manuel, Klein, Rüdiger, Giralt, Albert, del Toro, Daniel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.10.2024
• Subjects: Alzheimer’s disease; cortex expansion; DNA methylation; neurodegeneration; neurogenesis; rejuvenation; reprogramming; synapses; Yamanaka factor; reprogramming; Yamanaka factor; synapses; Alzheimer’s disease; cortex expansion; neurogenesis; neurodegeneration; DNA methylation; rejuvenation
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2024.09.013

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 spatiotemporal 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. Under these conditions, YF induction led to progenitor expansion, an increased number of upper cortical neurons and glia, and enhanced motor and social behavior in 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. These results highlight the powerful impact of YFs on neural proliferation and their potential use in brain disorders. [Display omitted] •Transient Yamanaka factor (YF) expression during development expands neocortex•YF-treated mice show enhanced cognitive skills•Intermittent YF expression is tolerated by adult principal hippocampal neurons•Long-term intermittent YF reprogramming is protective in an AD mouse model Shen and Zaballa et al. report on using Yamanaka factors (YFs) for partial reprogramming in the mouse brain. During development, YF induction results in cortical expansion and improved behavior. Similar induction at adult stages prevents the development of several Alzheimer’s disease hallmarks. These findings reveal YFs as a tool to increase neural proliferation and their potential use in brain disorders.