Expansion of the neocortex and protection from neurodegeneration byin vivotransient reprogramming

Abstract

SummaryYamanaka 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.HighlightsTransient Yamanaka factor (YF) expression during development expands neocortexYF-treated mice show enhanced cognitive skillsIntermitent YF expression is tolerated by adult principal hippocampal neuronsLong-term intermitent YF reprogramming is protective in an AD mouse model

Neuron-specific partial reprogramming in the dentate gyrus impacts mouse behavior and ameliorates age-related decline in memory and learning

“…This suggests that some of the benefits associated with partial reprogramming may be inherent to the neurons themselves, as it has been recently described for neurons of the subventricular zone (Xu et al, 2024). In this line, a recent study demonstrated that induction of neuron specific reprogramming during development improved cognitive function, and that partial reprogramming of hippocampal neurons at adult stages can also improve neurodegeneration phenotypes in an Alzheimer's mouse model (Shen et al, 2023). Importantly, our study includes older animals (18-26 months old), in which partial reprogramming of a subset of mature neurons in the DG was able to ameliorate age-related decline in memory and learning.…”

“…In the realm of brain rejuvenation, partial reprogramming has shown promising effects on several signatures associated with aging, such as memory improvement and enhanced production of neuroblasts, particularly in the subventricular zone (SVZ) (Rodriguez-Matellan et al, 2020;Xu et al, 2024). Furthermore, a recent study demonstrated that induction of neuron-specific reprogramming during development improved cognitive functions, and reprogramming hippocampal neurons at adult stages improved neurodegeneration phenotypes in an Alzheimer's mouse model (Shen et al, 2023).…”