Partial reprogramming involves the short-term expression of Yamanaka factors to restore youthful epigenetic control over nuclear DNA structure and gene expression. The primary challenge is to avoid accidental full reprogramming of cells into induced pluripotent stem cells, or otherwise losing necessary cell state, in a tissue environment in which different cell types require different degrees of exposure to pass various reprogramming-related thresholds. Interestingly, much of the present development of partial reprogramming as a basis for rejuvenation therapies has converged on the central nervous system as a target. For example, here researchers are interested in the neurons that encode memory, and find that partial reprogramming can improve memory function in aged mice.
Partial cellular reprogramming has emerged as one of the most promising strategies in regenerative medicine. Cyclic expression of the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc - OSKM), or a partial combination thereof (OSK), holds the potential to orchestrate rejuvenation of cellular function in aging while at the same time preventing changes in cell identity and tumorigenesis.
Memories are encoded in sparse neuronal ensembles termed engrams, which are found in different brain regions, with specific contributions to recall during memory consolidation. Thus, engrams in the hippocampus, and in particular in the dentate gyrus (DG), are predominantly important for learning and recent recall, whereas engrams in the medial prefrontal cortex (mPFC) become gradually more relevant for remote memory expression. Importantly, during physiological aging and in mouse models of Alzheimer's disease (AD), engram impairments interfere with memory recall, suggesting that engram dysfunction may underlie age- and disease-related memory decline.
Here, we report that partial reprogramming of engram neurons - bona fide memory trace cells - by OSK-mediated gene therapy reversed the expression of senescence-related and disease-related cellular hallmarks in aged mice and models of Alzheimer's disease (AD), re-established aberrant epigenetic-transcriptional patterns pertaining to synaptic plasticity, and counteracted AD-typical neuronal hyperexcitability. Importantly, irrespective of the brain area targeted or the behavioral paradigm employed, engram reprogramming also recovered learning and memory capacities to levels of healthy young animals, suggesting cognitive rejuvenation. These results posit that partial reprogramming of specific cell populations in the brain can be exploited for cognitive restoration in aging and disease.
Link: https://doi.org/10.1016/j.neuron.2025.11.028
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