Our ability to recall a past event – the smell of rain, the sound of a familiar voice – depends on tiny neural circuits called engrams. These are ensembles of brain cells that fire together during learning and must reactivate later for successful retrieval. But with advancing age, and even more so in neurodegenerative conditions like Alzheimer’s disease (AD), these engrams lose their spark. Their capacity for reactivation weakens, and memories slip away.
Now, a team of researchers in Switzerland has asked a bold question: can we rejuvenate those engrams by partially reprogramming them? Their answer, published in a recent study, points firmly to “yes.” By gently turning on just three of the four classic Yamanaka factors – proteins known to reset cellular age – they managed to restore memory in both elderly mice and a well-established mouse model of Alzheimer’s disease.
A Controlled Genetic Switch in the Hippocampus
The three factors used were Oct4, Sox2, and Klf4 (collectively abbreviated as OSK). Notably, the fourth classic Yamanaka factor, c-Myc, was omitted to avoid pushing cells all the way back to a stem‑cell state. The scientists engineered a doxycycline‑dependent system in the dentate gyrus of the mouse hippocampus, a region critical for memory formation. Removing doxycycline from the animals’ diet triggered OSK expression only in neurons that had just been activated during learning. To track these cells, they also made the engrams glow green (via GFP) under the control of the activity marker c‑Fos.
Experiments began with aged mice (9–10 months old) compared to young adults (2–3 months). The team used a standard fear‑conditioning paradigm: animals learned to associate a specific context with a mild foot shock. In the treated group, doxycycline was withdrawn precisely during the learning session and then restored immediately afterward. RNA analysis 90 minutes later confirmed that OSK was indeed active inside the hippocampal neurons that had encoded the fearful memory.
Old Mice Remember Like Young Ones Again
Two days after training, the mice were returned to the same context. Normal young mice show a characteristic “freezing” behavior – they stop moving when they recall the shock. Aged control mice, however, froze much less, indicating age‑related memory loss. But aged mice that had received OSK reprogramming behaved just like their young counterparts: their fear memory was fully restored.
When the researchers looked under the microscope, they found that engram neurons expressing Klf4 (a marker of reprogramming) were far more likely to reactivate than their non‑reprogrammed neighbours. Crucially, the reprogrammed neurons did not lose their identity. They continued to express Prox1, a hallmark of granular neurons of the dentate gyrus, showing that partial reprogramming rejuvenates function without erasing cell type.
Fighting Alzheimer’s‑Like Memory Deficits
Next, the team turned to APP/PS1 mice, a common model of familial Alzheimer’s disease. These animals develop cognitive impairments from middle age onward, but their fear memory remains relatively intact. So the researchers switched to a spatial memory test: the Morris water maze, where mice must learn the location of a hidden platform.
Untreated APP/PS1 mice took significantly longer to find the platform, showing poor spatial memory. In contrast, APP/PS1 mice that received hippocampal OSK expression learned the platform’s location as quickly as healthy controls. Partial reprogramming had rescued their ability to form and recall spatial maps.
What Happens Inside the Reprogrammed Neuron?
To understand the molecular basis of this improvement, the scientists performed single‑nucleus RNA sequencing and chromatin accessibility assays on engram cells. They discovered that OSK‑expressing neurons showed reduced molecular hallmarks of Alzheimer’s disease – for example, genes involved in synaptic plasticity were no longer suppressed.
Moreover, electrophysiological recordings revealed that partial reprogramming corrected a key abnormality: the hyperexcitability of engram neurons, a feature commonly seen in Alzheimer’s models. By calming this overactivity, OSK allowed the cells to fire in a more coordinated, memory‑friendly pattern.
A Path Toward Cognitive Rejuvenation
Taken together, these findings demonstrate that transient, partial reprogramming of engram neurons using OSK factors can reverse memory deficits in two distinct mouse models – physiological aging and Alzheimer’s pathology. The approach does not erase cell identity, does not require continuous treatment, and works on both fear‑based and spatial memories.
Of course, mice are not humans, and many questions remain: How long does the effect last? Could repeated cycles of reprogramming be harmful? And can OSK be delivered safely to the human brain? Nevertheless, the study opens a new avenue in the fight against age‑related cognitive decline and dementia – one where we might one day reboot our memory traces without losing who we are.
Publication date: 2026.02.27
Source: Berdugo-Vega G. et al. Cognitive rejuvenation through partial reprogramming of engram cells. Neuron. 2026 Mar 18;114(6):1102-1116.e7. doi: 10.1016/j.neuron.2025.11.028. Epub 2026 Feb 10. PMID: 41672073. https://www.cell.com/neuron/fulltext/S0896-6273(25)00925-0