Scientists from Cambridge and Leeds have successfully reversed memory loss linked to age in mice and say their discovery could lead to the development of treatments to prevent memory loss in people as they age.
In a study published today in Molecular Psychiatry, the team shows that changes in the brain’s extracellular matrix, “scaffolding” around nerve cells, lead to memory loss with aging, but that it is possible to reverse them using genetic treatments .
Recent evidence has emerged of the role of perineuronal networks (PNNs) in neuroplasticity, the ability of the brain to learn and adapt, and to create memories. PNNs are cartilage-like structures that primarily surround inhibitory neurons in the brain.
Their main function is to control the level of plasticity in the brain. They appear around the age of five in humans and deactivate the period of increased plasticity during which connections in the brain are optimized. Thus, plasticity is partially turned off, making the brain more efficient but less plastic.
PNNs contain compounds known as chondroitin sulfates. Some of these, such as chondroitin 4-sulfate, inhibit the action of networks, inhibiting neuroplasticity; others, such as chondroitin 6-sulfate, promote neuroplasticity.
As we age, the balance of these compounds changes, and as chondroitin 6-sulfate levels decline, our ability to learn and form new memories changes, leading to age-related memory decline.
Researchers at the University of Cambridge and the University of Leeds investigated whether manipulating the chondroitin sulfate composition of PNNs could restore neuroplasticity and relieve age-related memory deficits.
To do this, the team examined 20-month-old mice, considered very old, and using a series of tests showed that the mice showed deficits in their memory compared to the six-month-old mice.
For example, one test involved seeing if the mice recognized an object. The mouse was positioned at the beginning of a Y-shaped maze and allowed to explore two identical objects at the ends of the two arms. After a while, the mouse was placed back into the maze, but this time one arm contained a new object, while the other contained a copy of the repeating object.
The researchers measured the amount of time the mouse spent exploring each object to see if it had remembered the object of the previous activity. Older mice were less likely to remember the object.
Memory loss: viral vector already identified
The team treated the elderly mice using a “Viral vector”, a virus capable of replenishing the amount of chondroitin sulfate 6-sulfate to PNNs and found that this it completely restored the memory in older mice, to a similar level to that seen in younger mice.
Dr Jessica Kwok of the University of Leeds’ School of Biomedical Sciences said: “We saw remarkable results when we treated aged mice with this treatment. Memory and learning ability have been restored to levels from when they were much younger. “
To explore the role of chondroitin 6-sulfate in memory loss, the researchers bred mice that had been genetically manipulated in such a way that they were only able to produce low levels of the compound. to mimic the changes of aging.
Even at 11 weeks, these mice showed signs of premature memory loss. However, increasing chondroitin 6-sulfate levels using the viral vector restored memory and plasticity to levels similar to those of healthy mice.
Professor James Fawcett of the University of Cambridge’s John van Geest Center for Brain Repair said: “The interesting thing about this is that although our study was only in mice, the same mechanism should work in humans: the molecules and structures in the human brain are the same as those in rodents. This suggests that it may be possible to prevent humans from developing memory loss in old age. “
The team has already identified a potential drug, authorized for human use, that can be taken orally and inhibits PNN formation. When this compound is given to mice and rats, it can restore memory in aging and improve also recovery in spinal cord injuries.
Researchers are studying whether it could help alleviate memory loss in animal models of Alzheimer’s disease. The approach taken by Professor Fawcett’s team, using viral vectors to deliver the treatment, it is increasingly being used to treat human neurological conditions. A second team from the Center recently published research showing their use to repair the damage caused by glaucoma and dementia.
I study was funded by Alzheimer’s Research UK, Medical Research Council, European Research Council and Czech Science Foundation.