Scientists at Cambridge and Leeds have successfully reversed age-related
memory loss 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 show that
changes in the extracellular matrix of the brain -- 'scaffolding' around
nerve cells -- lead to loss of memory with ageing, but that it is possible
to reverse these using genetic treatments.
Recent evidence has emerged of the role of perineuronal nets (PNNs) in
neuroplasticity -- the ability of the brain to learn and adapt -- and to
make memories. PNNs are cartilage-like structures that mostly surround
inhibitory neurons in the brain. Their main function is to control the level
of plasticity in the brain. They appear at around five years old in humans,
and turn off the period of enhanced plasticity during which the connections
in the brain are optimised. Then, plasticity is partially turned off, making
the brain more efficient but less plastic.
PNNs contain compounds known as chondroitin sulphates. Some of these, such
as chondroitin 4-sulphate, inhibit the action of the networks, inhibiting
neuroplasticity; others, such as chondroitin 6-sulphate, promote
neuroplasticity. As we age, the balance of these compounds changes, and as
levels of chondroitin 6-sulphate decrease, so our ability to learn and form
new memories changes, leading to age-related memory decline.
Researchers at the University of Cambridge and University of Leeds
investigated whether manipulating the chondroitin sulphate composition of
the PNNs might restore neuroplasticity and alleviate age-related memory
deficits.
To do this, the team looked at 20-month old mice -- considered very old --
and using a suite of tests showed that the mice exhibited deficits in their
memory compared to six-month old mice.
For example, one test involved seeing whether mice recognised an object. The
mouse was placed at the start of a Y-shaped maze and left to explore two
identical objects at the end of the two arms. After a short while, the mouse
was once again placed in the maze, but this time one arm contained a new
object, while the other contained a copy of the repeated object. The
researchers measured the amount of the time the mouse spent exploring each
object to see whether it had remembered the object from the previous task.
The older mice were much less likely to remember the object.
The team treated the ageing mice using a 'viral vector', a virus capable of
reconstituting the amount of 6-sulphate chondroitin sulphates to the PNNs
and found that this completely restored memory in the older mice, to a level
similar to that seen in the younger mice.
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."
To explore the role of chondroitin 6-sulphate in memory loss, the
researchers bred mice that had been genetically-manipulated such that they
were only able to produce low levels of the compound to mimic the changes of
ageing. Even at 11 weeks, these mice showed signs of premature memory loss.
However, increasing levels of chondroitin 6-sulphate using the viral vector
restored their memory and plasticity to levels similar to healthy mice.
Professor 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."
The team have already identified a potential drug, licensed for human use,
that can be taken by mouth and inhibits the formation of PNNs. When this
compound is given to mice and rats it can restore memory in ageing and also
improves recovery in spinal cord injury. The researchers are investigating
whether it might help alleviate memory loss in animal models of Alzheimer's
disease.
Reference:
Sujeong Yang, Sylvain Gigout, Angelo Molinaro, Yuko Naito-Matsui, Sam
Hilton, Simona Foscarin, Bart Nieuwenhuis, Chin Lik Tan, Joost Verhaagen,
Tommaso Pizzorusso, Lisa M. Saksida, Timothy M. Bussey, Hiroshi Kitagawa,
Jessica C. F. Kwok, James W. Fawcett. Chondroitin 6-sulphate is required for
neuroplasticity and memory in ageing. Molecular Psychiatry, 2021; DOI:
10.1038/s41380-021-01208-9
Tags:
Medical Science