Summary: Controlled expression of the Yamanaka factors can reverse signs of aging in brain neurons, restoring synaptic connections, normalizing metabolism, and providing protection against neurodegenerative processes such as those seen in Alzheimer’s disease. In adult mice, delivering these factors to neurons led to cellular rejuvenation without observable side effects and corresponded with improved motor and social behaviors.
This research advances the potential of cellular reprogramming as a therapeutic strategy for neurodegenerative disorders by demonstrating that mature neurons can regain youthful molecular and functional traits when exposed to carefully regulated cycles of Yamanaka factor expression.
Key facts:
- Yamanaka factors (Oct4, Sox2, Klf4, c-Myc) can rejuvenate cortical neurons, increasing synaptic connectivity and stabilizing cellular metabolism.
- Transient, controlled induction during development expands cortical cell populations and improves motor and social behaviors in adult mice.
- Targeted expression in mature neurons of adult mice prevented several hallmarks of Alzheimer-like neurodegeneration in an experimental model.
Source: University of Barcelona
When neurons age, they lose synaptic contacts, transmit signals less effectively, and undergo metabolic changes that compromise function. This decline contributes to vulnerability in neurodegenerative diseases such as Alzheimer’s disease.
A study led by researchers at the University of Barcelona shows that these age-related alterations can be mitigated in mice by applying a precisely controlled cellular reprogramming protocol based on the Yamanaka factors. The work highlights novel ways to recover neuronal properties and suggests new avenues for treating neurodegenerative conditions.
Published in Cell Stem Cell, the study is led by Daniel del Toro and Albert Giralt (University of Barcelona), together with Rüdiger Klein (Max Planck Institute for Biological Intelligence). The work also includes contributions from Sofía Zaballa and Manuel Serrano.
Rejuvenating cortical neurons with Yamanaka factors
The Nobel-recognized Yamanaka factors—Oct4, Sox2, Klf4 and c-Myc—reprogram differentiated cells toward a more pluripotent state. While prior research has largely explored their effects in peripheral tissues such as skin, muscle, liver and heart, this study focuses on how Yamanaka factor-driven reprogramming affects the central nervous system.
The team investigated controlled, low-level, transient expression of Yamanaka factors in two scenarios: during brain development and in adult animals, including a mouse model of Alzheimer’s disease. Del Toro reports that introducing these factors broadly during developmental stages expanded neural progenitors and increased the number of neurons and glia in the cortex, producing larger cortical volume and measurable improvements in motor and social behaviors in adulthood.
When Yamanaka factors were induced specifically in mature, non-dividing neurons of adult mice, the cells did not proliferate but showed clear markers of rejuvenation. According to Giralt, rejuvenated neurons exhibited increased synaptic contacts, restored metabolic stability, and a normalized epigenetic profile—changes that translated into better neuronal function and protection in the Alzheimer-like model used in the study.
Cellular reprogramming as a strategy against neurodegeneration
Understanding and reversing cellular aging in neurons opens promising therapeutic opportunities, but reprogramming carries risks, including the potential for uncontrolled cell growth. The authors emphasize that spatially and temporally precise control of Yamanaka factor expression was critical: by targeting specific neural populations and using transient, low-level induction, they avoided tumorigenic outcomes while enhancing synaptic plasticity and higher-order behaviors such as social interaction and memory formation.
Mechanistically, the effects of Yamanaka factors in the nervous system appear to operate across multiple molecular layers: they reshape epigenetic marks that influence gene transcription, stabilize mitochondrial and metabolic pathways linked to cellular energy management, and modulate genes and signaling networks that govern synaptic plasticity.
This work builds on previous findings that Yamanaka factors can promote regeneration after injury in retinal ganglion cells and induce epigenetic changes in hippocampal neurons. The new results emphasize their potent role in neural proliferation during development and in protecting mature neurons from degenerative signatures.
The researchers conclude that further studies should identify which neurological diseases might benefit from controlled reprogramming, elucidate the precise molecular mechanisms at play, and develop safe therapeutic strategies that could eventually be translated toward clinical applications.
About this neuroscience research news
Author: Rosa Martínez
Source: University of Barcelona
Contact: Rosa Martínez – University of Barcelona
Image: The image is credited to Neuroscience News
Original research (open access): “Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming” by Daniel del Toro et al., Cell Stem Cell.
Abstract
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 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.