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Age-related memory loss reversed in mice by scientists in Cambridge and Leeds

Scientists have reversed age-related memory loss in mice – and believe it could be used to develop treatment to prevent the problem in humans.

Conceptual image of interconnected neurons
Conceptual image of interconnected neurons

The researchers at the University of Cambridge and University of Leeds found “remarkable” results in mice and are now testing their technique to see if it will alleviate memory loss in animal models of Alzheimer’s disease. Their study, published in Molecular Psychiatry, explains how changes in the ‘scaffolding’ around nerve cells in the brain – known as the extracellular matrix – lead to loss of memory with ageing, but genetic treatments can be used to reverse it.

It follows recent evidence of the role of perineuronal nets (PNNs) in the ability of the brain to learn and adapt – known as its neuroplasticity – and to make memories.

These PNNs are cartilage-like structures mostly surrounding inhibitory neurons in the brain

When they appear, at around five years old in humans, they turn off a period of enhanced plasticity during which the connections in the brain are optimised. This makes the brain more efficient but less plastic.

They contain compounds known as chondroitin sulphates and some, such as chondroitin 4-sulphate, inhibit the action of the networks, to reduce neuroplasticity, while others, such as chondroitin 6-sulphate, promote it.

The balance of these compounds changes as we age. As levels of chondroitin 6-sulphate decrease, our ability to learn and form new memories changes, which leads to age-related memory decline.

The researchers tested whether manipulating the chondroitin sulphate composition of the PNNs might restore neuroplasticity and alleviate these age-related memory deficits. They compared the memory of 20-month-old mice – considered elderly – with six-month-old ones using tests such as object recognition in mazes. Older mice proved much less likely to remember an object. But then they treated the ageing mice using a viral vector – in this case, a virus capable of reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs.

Dr Jessica Kwok, from the School of Biomedical Sciences at the University of Leeds, said: “We saw remarkable results when we treated the ageing mice with this treatment. The memory and ability to learn were restored to levels they would not have seen since they were much younger.”

The researchers bred mice that had been genetically-manipulated so they could only produce low levels of chondroitin 6-sulphate to mimic the changes of ageing. They showed signs of premature memory loss even at 11 weeks. But increasing levels of the compound using the viral vector restored their memory and plasticity to levels similar to healthy mice.

Prof James Fawcett, from the John van Geest Centre for Brain Repair at the University of Cambridge, said: “What is exciting about this is that although our study was only in mice, the same mechanism should operate 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.”

They have identified a potential drug, already licensed for human use, that can be taken by mouth which inhibits the formation
of PNNs.

When given to mice and rats it can restore memory in ageing and improves recovery in spinal cord injury, so the researchers are investigating whether it might help alleviate memory loss in animal models of Alzheimer’s disease.

The use of viral vectors has also been used by a second team at the centre in research on repairing the damage caused by glaucoma and dementia.

The latest study, published in Molecular Psychiatry, was funded by Alzheimer’s Research UK, the Medical Research Council, European Research Council and the Czech Science Foundation.

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