In vivo partial neuronal reprogramming reverses age-associated phenotypes and enhances memory performance

In recent years, there has been success in reverting peripheral organ cells to earlier epigenetic states without full dedifferentiation. This has been achieved through in vivo partial reprogramming of peripheral organ cells using cyclic expression of Yamanaka transcription factors (YF), resulting in the reversal of age-related pathologies. In the case of the brain, the effects of partial reprogramming are scarcely known, and only some of its effects have been observed through the widespread expression of YF. This is the first study to achieve exclusive partial reprogramming of neurons from cerebral cortex, allowing for a precise in vivo assessment of the impact of this strategy on one of the major components of the brain. In this study, in vivo partial reprogramming of a specific subpopulation of neurons in middle-aged mice has been achieved through the inducible and cyclical expression of YF. In contrast to the continuous and ubiquitous expression of YF, their induction in adult mice restricted only to a-CamKII-expressing neurons has not shown deleterious effects on mice as increased proliferation or decreased survival rates. Furthermore, this model has demonstrated the efficacy of partial neuronal reprogramming solely through cyclic expression of YF, leading to a significant improvement in cognitive function in adult mice. Increased neuronal activation associated with memory performance, and plasticity, by the reorganisation of the extracellular matrix, have been observed. Moreover, epigenetic markers associated with ageing, such as H4K20me3, were reversed in cortical neurons where partial reprogramming takes place. The results obtained support the potential of targeted partial reprogramming of a-CamKII-expressing neurons in reversing age-associated phenotypes and enhancing cognition, highlighting the therapeutic potential that this type of strategy could have in addressing neurodegenerative diseases correlated with aging.