̽��ֱ�� of Cambridge - James Fawcett

Scientists reverse age-related memory loss in mice

sc604 — Thu, 22 Jul 2021 14:18:03 +0000

In a study published 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 ̽��ֱ�� of Cambridge and ̽��ֱ�� 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. ̽��ֱ��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. ̽��ֱ��researchers measured the amount of time the mouse spent exploring each object to see whether it had remembered the object from the previous task. ̽��ֱ��older mice were much less likely to remember the object.

̽��ֱ��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 ̽��ֱ�� of Leeds said: “We saw remarkable results when we treated the ageing mice with this treatment. ̽��ֱ��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 ̽��ֱ�� 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.”

̽��ֱ��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. ̽��ֱ��researchers are investigating whether it might help alleviate memory loss in animal models of Alzheimer's disease.

̽��ֱ��approach taken by Professor Fawcett’s team – using viral vectors to deliver the treatment – is increasingly being used to treat human neurological conditions. A second team at the Centre recently published research showing their use for repairing damage caused by glaucoma and dementia.

̽��ֱ��study was funded by Alzheimer’s Research UK, the Medical Research Council, European Research Council and the Czech Science Foundation.

Reference
Yang, S et al. Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. Molecular Psychiatry; 16 July 2021; DOI: doi.org/10.1038/s41380-021-01208-9

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.

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

James Fawcett

Michael Shribak, Marine Biological Laboratory, Woods Hole, MA

Spatially oriented neurons (mouse brain)

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Technique to regenerate the optic nerve offers hope for future glaucoma treatment

cjb250 — Thu, 05 Nov 2020 10:00:30 +0000

Axons – nerve fibres – in the adult central nervous system (CNS) do not normally regenerate after injury and disease, meaning that damage is often irreversible. However, over the past decade there have been a number of discoveries that suggest it may be possible to stimulate regeneration.

In a study published today in Nature Communications, scientists tested whether the gene responsible for the production of a protein known as Protrudin could stimulate the regeneration of nerve cells and protect them from cell death after an injury.

̽��ֱ��team, led by Dr Richard Eva, Professor Keith Martin and Professor James Fawcett from the John van Geest Centre for Brain Repair at the ̽��ֱ�� of Cambridge, used a cell culture system to grow brain cells in a dish. They then injured their axons using a laser and analysed the response to this injury using live-cell microscopy. ̽��ֱ��researchers found that increasing the amount or activity of Protrudin in these nerve cells vastly increased their ability to regenerate.

Nerve cells in the retina, known as retinal ganglion cells, extend their axons from the eye to the brain through the optic nerve in order to relay and process visual information. To investigate whether Protrudin might stimulate repair in the injured CNS in an intact organism, the researchers used a gene therapy technique to increase the amount and activity of Protrudin in the eye and optic nerve. When they measured the amount of regeneration a few weeks after a crush injury to the optic nerve, the team found that Protrudin had enabled the axons to regenerate over large distances. They also found that the retinal ganglion cells were protected from cell death.

̽��ֱ��researchers showed that this technique may help protect against glaucoma, a common eye condition. In glaucoma, the optic nerve that connects the eye to the brain is progressively damaged, often in association with elevated pressure inside the eye. If not diagnosed early enough, glaucoma can lead to loss of vision. In the UK, round one in 50 people over the age of 40, and one in ten people over the age of 75 is affected by glaucoma.

To demonstrate this protective effect of Protrudin against glaucoma, the researchers used a whole retina from a mouse eye and grew it in a cell-culture dish. Usually around a half of retinal neurons die within three days of retinal removal, but the researchers found that increasing or activating Protrudin led to almost complete protection of retinal neurons.

Dr Veselina Petrova from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge, the study’s first author, said: “Glaucoma is one of leading causes of blindness worldwide. ̽��ֱ��causes of glaucoma are not completely understood, but there is currently a large focus on identifying new treatments by preventing nerve cells in the retina from dying, as well as trying to repair vision loss through the regeneration of diseased axons through the optic nerve.

“Our strategy relies on using gene therapy – an approach already in clinical use – to deliver Protrudin into the eye. It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow. It’s important to point out that these findings would need further research to see if they could be developed into effective treatments for humans.”

Protrudin normally resides within the endoplasmic reticulum, tiny structures within our cells. In this study, the team showed that the endoplasmic reticulum found in axons appears to provide materials and other cellular structures important for growth and survival in order to support the process of regeneration after injury. Protrudin stimulates transport of these materials to the site of injury.

Dr Petrova added: “Nerve cells in the central nervous system lose the ability to regenerate their axons as they mature, so have very limited capacity for regrowth. This means that injuries to the brain, spinal cord and optic nerve have life-altering consequences.

“ ̽��ֱ��optic nerve injury model is often used to investigate new treatments for stimulating CNS axon regeneration, and treatments identified this way often show promise in the injured spinal cord. It’s possible that increased or activated Protrudin might be used to boost regeneration in the injured spinal cord.”

̽��ֱ��research was supported by the Medical Research Council, Fight for Sight, the Bill and Melinda Gates Foundation, Cambridge Eye Trust and the National Eye Research Council.

Reference
Petrova, V et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Comms; 5 Nov 2020; DOI: 10.1038/s41467-020-19436-y

Scientists have used gene therapy to regenerate damaged nerve fibres in the eye, in a discovery that could aid the development of new treatments for glaucoma, one of the leading causes of blindness worldwide.

It’s possible our treatment could be further developed as a way of protecting retinal neurons from death, as well as stimulating their axons to regrow

Veselina Petrova

TobiasD

Eye

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Spinal injury and ‘biorobotic control’ of the bladder

cjb250 — Tue, 16 Feb 2016 13:27:49 +0000

Spinal cord injury is, in many respects, a testosterone disease, says Professor James Fawcett.

What he means by this is that four out of five spinal cord injuries happen to men, and the most common age group is early adulthood. “Men are not good at assessing risk at that age,” he says. “Females are much more sensible.”

It is perhaps not surprising, then, that when asked about their priorities, most quadriplegic people will select a return of sexual function as second after the use of arms and hands. Third on the list, above being able to walk, is a return of bladder and bowel control. “Way down the list is walking, because wheelchairs work reasonably well and patients can get used to using them,” says Fawcett, who heads the John van Geest Centre for Brain Repair at Cambridge.

Restoring bladder and bowel control is a particular challenge, however. Currently, patients have to fill their bladder with botulinum toxin (botox) to paralyse it and catheterise themselves several times a day. This may be the simplest method, but catheterisation can cause infection and scarring in the urethra.

Instead, Fawcett is developing a device based on the ‘Brindley device’, named after physiologist Giles Brindley, who trained at Cambridge after the Second World War. ̽��ֱ��Brindley device is an implant to which an external stimulator is applied manually, causing the bladder to contract and empty itself. It has been used in thousands of patients, but it, too, is not without problems: it necessitates severing sensory nerves from the pelvis into the spinal cord, causing weakening of the pelvic muscles – and loss of sexual function. (For most male patients, Viagra can at least help them maintain an erection, but this is only half the problem. ‘Well OK, doc,’ they say, ‘you’ve given me an erection, but what’s the use if I can’t feel it?’”)

Fawcett and colleagues are developing a ‘biorobotic’ version of the Brindley device that can read signals from the sensory nerves in the pelvis, rather than requiring them to be cut. These signals would stop the bladder emptying itself at embarrassing times, tell the patient how full the bladder is, and allow them to use the electronics to empty it.

̽��ֱ��ability to record signals from individual nerves has applications beyond just bladder control: Fawcett envisioned the technology as enabling patients who had lost a limb – such as soldiers losing arms or legs – to control robotic limbs. “ ̽��ֱ��limbs themselves are quite sophisticated,” he says, “but what doesn’t work at all well is their interface with the nervous system.” ̽��ֱ��technology required for recording signals for a whole limb has proven to be extremely complicated, so the team is looking at the bladder-control device as a simpler demonstration of a proof of concept.

Biorobotics will be one focus of a proposed new Spinal Injury Research Centre to be based at Addenbrooke’s Hospital. Although still at the very early planning stages, the Centre will capitalise on Cambridge’s position as the regional trauma centre for the East of England (even though a lack of facilities means spinal injury patients have to be sent to Stoke Mandeville near Oxford for rehabilitation).

A simplified version of the adapted Brindley device has so far been trialled in around 50 dogs, in whom spinal cord injury is surprisingly common, particularly in dogs with longer spines, such as dachshunds. Many owners of injured dogs want to keep their pets but, as Fawcett explains, “the dogs are perfectly happy to paddle around with wheels under their back legs, but they do so dribbling urine around your house.”

In fact, a randomised controlled trial in 2013 showed that injured dogs may even be able to do away with their wheels. Professor Robin Franklin from the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute showed that transplanting cells found in the nasal cavity, known as olfactory ensheathing cells, into the injured spine could help restore movement to the previously paralysed limbs. Although the cell transplant did not restore bowel or bladder control, it was, says Franklin, “a landmark study” that offers the promise of translation into humans. Franklin’s colleague Dr Mark Kotter is currently seeking funding to carry out a trial in humans.

But as Fawcett says, the priority among injured patients is to recover use of their upper limbs. Spinal cord injury causes damage to motor nerve fibres travelling from the brain and to sensory nerve fibres travelling to the brain. Both are structurally different and need to be coaxed to regenerate across the site of the injury – but even getting the nerve fibres to span these couple of centimetres is a challenge.

“ ̽��ֱ��problem is scar tissue,” says Fawcett. “It’s very difficult for nerve fibres to grow through this tissue.” He has identified an enzyme, chondroitinase, which can dissolve scar tissue. ̽��ֱ��enzyme works in rats and is in preclinical development for use in humans by the US biotech company Acorda Therapeutics.

Once the scar tissue has been dissolved, the nerve fibres need to regenerate and make new connections. Although restoring motor nerve fibres is proving a challenge, Fawcett has managed to restore sensory nerve fibres in rats, which is an important start. “Patients need to be able to feel what they’re doing and to sense pain. If they turn on a hot tap, they can easily scald themselves if they can’t feel the heat. And of course, they want sensation back in their genitalia.”

In most spinal cord injuries, some nerve fibres will always survive, and Fawcett believes we may be able to harness these to bypass nerve damage if we can harness a remarkable property of the young brain known as plasticity, which enables new connections to be made as we learn new skills. If a young child receives a spinal injury, their chances of recovery are much better than for an adult as their brain can adapt, but as we age, a cartilage-like coating wraps around nerve fibres, cementing the connections in place. These molecules make it difficult for the brain of an injured adult to find a way to bypass the injury.

“Interestingly,” explains Fawcett, “one of the main constituents of this cartilage is the same as that which blocks nerve growth in scar tissue – and we know we can dissolve this using chondroitinase. This should make rehabilitation – teaching the brain to do useful things again – dramatically more successful.”

Inset image: Credit ̽��ֱ��District.

There are many challenges facing people with spinal cord injury – and walking again is often the least of their problems. Cambridge research could help patients take control of their lives once more.

This should make rehabilitation – teaching the brain to do useful things again – dramatically more successfull.

James Fawcett

Zeevveez

Wheelchair

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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