Scientists at EPFL have found a way to restore memory in older mice and those with Alzheimer's-like conditions by briefly turning on three specific genes in certain brain cells. Memory loss from aging or diseases like Alzheimer's is often seen as permanent, but the brain can adapt. Neurons change their connections through synaptic plasticity - the ability of these connections to strengthen or weaken for learning and remembering. However, aging and Alzheimer's harm the processes that keep this flexibility going.
Memories depend on engrams, sparse groups of neurons that activate during learning and replay for recall. In older or diseased brains, these engrams fail, leading to poor memory. The researchers wondered if refreshing these engram neurons could fix memory after problems start. They used a method called partial reprogramming, briefly activating genes known as OSK (Oct4, Sox2, and Klf4) just in the engram neurons tied to learning, not the whole brain.
To do this, they used gene therapy with viruses injected into the brain. They tagged neurons active during learning with a fluorescent marker and added a switch to turn OSK on for a short time. They focused on key areas: the dentate gyrus in the hippocampus, a region vital for forming and recalling recent memories, and the medial prefrontal cortex, which handles memories from weeks ago.
Testing the approach
In aged mice, activating OSK in hippocampal engram neurons brought memory back to young levels. Doing the same in the prefrontal cortex fixed older memories. The treated neurons looked healthier, with traits of younger cells, like better nuclear structure.
In Alzheimer's model mice, which struggle with navigation and memory tasks, reprogramming dentate gyrus engrams improved learning, while prefrontal targeting restored long-term recall. Gene activity and neuron firing linked to Alzheimer's improved too.
This work shows that targeting a few memory neurons briefly can reverse decline without broad risks, proving the concept for future therapies.
This research is published in Neuron.