Cellular Reprogramming Rescues Memory-Encoding Neurons

Scientists have applied partial reprogramming to memory-encoding neurons (engrams) and achieved memory improvements in Alzheimer’s models and wild-type mice [1].

Rejuvenating neurons

Partial cellular reprogramming, which uses certain factors to rejuvenate cells while maintaining their identity) has shown promise across various conditions and cell types, including neurons [2]. Rejuvenating these long-lived brain cells is imperative for achieving meaningful life extension, since, unlike most organs, the brain cannot be simply replaced.

In a new study published in Neuron, a team of researchers from the Swiss Federal Technology Institute of Lausanne (EPFL) achieved targeted reprogramming of engram cells, the specific neurons that encode memories. The team used three of the four Yamanaka factors, Oct4, Sox2, and Klf4, to create the reprogramming cocktail OSK; cMyc was left out. This “abridged” formula supposedly allows for safer reprogramming without de-differentiation and is analogous to the one used in the upcoming very first clinical trial of cellular reprogramming in humans.

The team built a clever dual-AAV system, with one virus carrying a transcriptional activator that turns on during learning and the other encoding the OSK factors. The entire system is gated by doxycycline: removing it from drinking water opens a labeling window around the learning event so that only neurons active during learning get tagged and reprogrammed. Doxycycline is then reintroduced to shut off expression.

The team began with 9- to 10-month-old mice, which, like humans, exhibit age-related declines in cognitive abilities. Aged animals showed decreased freezing (representing worse memorization of danger) compared to young mice, confirming age-related memory impairment. OSK-injected aged mice were rescued to young-like freezing levels. Importantly, reprogrammed hippocampal engrams were preferentially reactivated upon recall compared to non-reprogrammed ones, suggesting specific enhancement of the functional cells.

The reprogramming also reversed age-related cellular hallmarks while preserving neuronal fate. “These results suggest that OSK induction does not lead to a loss in cell identity but rather strengthens it,” the paper says.

Memory improvements

To test whether the effect extends to remote memory, which depends on the medial prefrontal cortex (mPFC) rather than the hippocampus [3], the team targeted mPFC engrams in a separate cohort of aged mice using the same system. Again, aged controls showed impaired freezing, while OSK-injected aged mice did not. The researchers detected restoration of identity and functional markers, demonstrating that the effect is not region-specific.

Next, they moved to APP/PS1 mice, which develop amyloid pathology and memory deficits and are often used as an Alzheimer’s disease model. In a five-day water maze test, control APP/PS1 mice showed reduced use of spatial search strategies and took longer paths compared to wild type controls, indicating cognitive and memory impairment. OSK-injected APP/PS1 animals showed significantly increased use of spatial strategies and took shorter paths. Basically, while wild-type Alzheimer’s mice got stuck using random-like strategies, OSK-treated Alzheimer’s mice regained normal learning progression. Here too, the experiments targeted both hippocampal and mPFC engrams, with comparable results.

“This paper directly addresses a big fear of brain reprogramming – ‘won’t it scramble memories?’ They target learning-activated engram neurons, test recall two days later, and see the opposite of memory erasure: memory is rescued,” said Yuri Deigin, CEO of YouthBio, which is gearing up for its own clinical trials of partial reprogramming in Alzheimer’s. “Moreover, they explicitly ask whether OSK causes dedifferentiation, and the identity readouts move the other way, suggesting identity is being reinforced, not lost. And they don’t just show a short-term bump: they restore remote memory at two weeks via mPFC engrams.” Deigin and YouthBio were not involved in this study.

Reduced biological age

Finally, the team built a regression model using learning metrics from the water maze to predict chronological age in mice. This model achieved moderate power (R = 0.57), predicting age with a median error of 10 weeks. When applied to OSK-injected aged wild-type mice, it showed a significant reduction in predicted cognitive age. For Alzheimer’s mice (two different models – APP/PS1 and 5xFAD), non-treated animals showed accelerated cognitive aging, while OSK-injected mice returned to chronological age levels.

One important nuance is that in the OSK system the researchers used, the reprogramming and learning events are necessarily simultaneous; the labeling strategy can only identify engram neurons at the moment they fire during encoding, so there is no way to target OSK to those cells in advance. Therefore, the cognitive benefits likely arise less from improved encoding of memories and more from better recall, as engram neurons undergo rejuvenation during the days to weeks after learning. In principle, if engram neurons could be identified while quiescent, pre-treating them with OSK before a learning challenge might yield even stronger effects.

“On a personal note, it’s validating,” said Deigin. “I proposed back in 2019 that partial reprogramming could counteract Alzheimer’s and age-related cognitive decline, and we built YouthBio Therapeutics around that hypothesis. There are now multiple independent mouse studies pointing in the same direction. Biology R&D moves slowly, but the implications are profound: partial reprogramming may be disease-modifying well beyond Alzheimer’s.”

Literature

[1] Berdugo-Vega, G., Sierra, C., Astori, S., Calati, V., Orsat, J., Scoglio, M. J., Sandi, C., & Gräff, J. (2026). Cognitive rejuvenation through partial reprogramming of engram cells. Neuron. Advance online publication.

[2] Antón-Fernández, A., Roldán-Lázaro, M., Vallés-Saiz, L., Ávila, J., & Hernández, F. (2024). In vivo cyclic overexpression of Yamanaka factors restricted to neurons reverses age-associated phenotypes and enhances memory performance. Communications Biology, 7(1), 631.

[3] Frankland, P. W., & Bontempi, B. (2005). The organization of recent and remote memories. Nature reviews neuroscience, 6(2), 119-130.