Geneticists have found a way to restore memory in aging and Alzheimer’s disease

It is generally believed that age-related memory impairment or such severe diagnoses as Alzheimer’s disease are irreversible processes. However, our brain is not a fixed structure. Neurons are constantly adjusting the strength of their connections, and it is this flexibility, called synaptic plasticity, that underlies our ability to remember new information. Unfortunately, over the years, this mechanism fails.

Specific groups of neurons called engrams serve as the basis for storing memories. They activate when we learn something, and light up again when we need to remember it, forming a kind of memory trace. In an aging brain, these circuits begin to work incorrectly, which is why access to the experience is lost.

A team from the EPFL Brain Institute, led by Johannes Graff, decided to test a bold hypothesis: is it possible to fix a broken mechanism if these cells are specifically rejuvenated? In the article, the authors declare success. They were able to restore cognitive abilities in mice by “partially reprogramming” neurons using a cocktail of three genes (Oct4, Sox2, and Klf4) known as OSK.

It was previously known that these factors can reset the age markers in cells, returning them to a more youthful state. The innovation of the current approach was that the impact was not directed at the entire brain, but specifically only at the very engrams responsible for learning.

To implement the plan, the specialists used methods of gene therapy. A special system was delivered to the brains of rodents using viral vectors.: she marked the neurons active during learning with a glowing indicator and triggered the production of OSK proteins in them. Moreover, the inclusion of these genes occurred only for a short period of time.

The effect of therapy in the dentate gyrus of the hippocampus (the area responsible for recent memories) was amazing. Older animals began to cope with tasks at the level of their young relatives. When the technique was applied to the prefrontal cortex, the mice were able to regain even those memories that had been formed a few weeks ago and were considered lost.

In-depth tissue analysis showed clear signs of neuronal healing. The cells retained their identity, but their molecular characteristics changed. The structure of the cell nucleus, which usually deforms with age, began to look the same as in young individuals.

The project is particularly important in the context of the fight against neurodegenerative disorders. Experimental mice with a model of Alzheimer’s disease initially suffered from poor navigation and could not remember routes. After reprogramming the engrams in the hippocampus and cortex, their learning strategies improved, and long-term spatial memory was restored.

This experience serves as an important proof of concept: memory function can be restored even after the onset of cognitive decline. The main secret of success lies in precision — the effect is on a small number of cells and for a limited time, which allows you to benefit without the risk of disrupting the rest of the brain.