Partial reprogramming restored memory in aged and Alzheimer’s mice
A Neuron study reported that partial reprogramming of engram neurons with OSK restored memory in aged mice and improved learning and long-term memory in Alzheimer’s mouse models.
Partial reprogramming of engram neurons restored memory performance in multiple mouse settings, according to a study published in Neuron. Using a short, controlled pulse of three genes — Oct4, Sox2 and Klf4, referred together as OSK — researchers at EPFL’s Brain Mind Institute restored learning and memory in aged mice and improved memory-related impairments in mouse models of Alzheimer’s disease.
The team targeted OSK specifically at the engram neurons that are active during learning, rather than broadly across the entire brain. Working on mice, the researchers used gene therapy vectors delivered by precise brain injections and combined a system that adds a fluorescent tag to neurons that are activated by learning with a switch that briefly turns OSK on during a defined time window.
The approach was used in brain areas known to support different kinds of memory: the dentate gyrus of the hippocampus, which is important for learning and recent recall, and the medial prefrontal cortex, which contributes to remote recall two weeks later. In aged mice, briefly activating OSK in learning-related hippocampal engram neurons restored memory, essentially bringing performance back to levels seen in young controls. When the same approach was applied to prefrontal cortex engrams, it also recovered remote memories formed weeks earlier.
The researchers found that reprogrammed engrams displayed molecular behavior of more youthful cells. The reprogrammed engram neurons maintained their neuronal identity and displayed molecular features associated with a younger state, including changes in nuclear structure linked to aging. Further analysis revealed that Alzheimer’s-related changes in gene activity and neuronal firing within engram cells were partly reversed by turning OSK on.
The team then tested mouse models of Alzheimer’s disease. In a spatial-learning task, the mice showed inefficient navigation and impaired memory strategies. Reprogramming dentate gyrus engrams improved learning strategies during training, while targeting prefrontal engrams restored long-term spatial memory.
The study stands as a proof of concept for restoring function in a specific group of memory-related neurons to improve memory performance, even after cognitive decline has begun. By limiting OSK expression to a small number of neurons and a short time window, the approach captures beneficial effects while reducing the risk of disrupting cell functions.