Researchers have developed a new strategy to rescue age-related memory impairment in mice with gene therapy, which involves restoring the balance of chondroitin sulphates in the brain.
Perineuronal nets (PNNs) are extracellular matrix structures surrounding neurons in the brain. They control the ability of neural networks to grow and reorganise, described as neuroplasticity. This is an ongoing process that allows us to learn, adapt and form memories throughout our lives.
Specifically, neuroplasticity is controlled by sulphated chondroitin sulphates within the PNNs. There are two predominant types of chondroitin sulphates in the central nervous system. Chondroitin 6-sulphate (C6S) promotes neuroplasticity, while chondroitin 4-sulphate (C4S) is inhibitory. Over time, the proportion of C6S diminishes and results in an increase in the C4S/C6S ratio. Consequently, PNNs become increasingly inhibitory with age and the ability to form memories declines, leading to age-related memory impairment.
Chondroitin sulphates and memory
In a collaboration between researchers from the University of Cambridge and University of Leeds, a recent study investigated whether altering the composition of chondroitin sulphates in PNNs would restore neuroplasticity and reverse age-related memory decline. The findings have recently been published in Molecular Psychiatry.
The researchers first used three memory tests on aged 20-month-old mice to assess place memory and exploratory responses to a new environment. Compared to young 6-month-old mice, the aged mice demonstrated memory deficits in all of the tests.
By injecting chondroitinase, which completely digests C4S and C6S, into aged mouse brains, they further showed that chondroitin sulphates in the PNNs contributes to memory deficit. Treated mice exhibited memory retention to a level similar to that observed in young mice. Aged mouse brains were also shown to have reduced C6S levels, resulting in a predominance of inhibitory C4S.
Gene therapy for age-related memory impairment
To test if C6S loss causes age-related memory impairment, the researchers then generated young C6 sulfotransferase-1 (chst3) knockout mice. chst3 is the enzyme that makes C6S. The knockouts demonstrated progressive memory deficits in all three memory tests, suggesting that low C6S levels impair memory.
These observations suggest that reconstituting C6S in the PNNs to the amounts seen in younger mice can rescue memory in aged mice. To confirm this, the researchers delivered the chst3 gene into chst3-knockout aged mice via a viral vector. chst3 overexpression restored memory in aged mice to levels seen in young mice.
Overall, this study has demonstrated that restoring the C4S/C6S balance in the brain may be able to treat neurological conditions. Professor James Fawcett, one of the researchers from 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.”
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