Brain Awareness Week — studying the power of the brain’s self-cleaning system

At Parkinson’s UK, almost all of the research we fund relates to the brain in some way. We know the symptoms of Parkinson’s are caused by a loss of a brain chemical called dopamine. This is linked to the death of brain cells which produce it. So whether the research is studying the brain more closely to look at what causes this, studying the impact of certain drugs for treating symptoms. Or even studying the effects of certain activities such as physical activity on mental health, it would be tricky to study Parkinson’s without considering the brain along the way.

Some of the projects we fund look a bit more closely at how the condition develops in the brain. One such project is being led by Dr Ian Harrison and Professor Mark Lythgoe at University College London.

Ian and Mark are interested in how our brains normally get rid of waste products which build up throughout the day. Failed clearance of these waste products can lead to them building up in the brain, which can stop the cells from being able to carry out their job as usual.

Many different neurodegenerative conditions are associated with a build-up of brain waste, normally in the form of clumps of sticky protein. In Parkinson’s, the troublesome protein is called alpha-synuclein. Strands of the protein start to tangle together and clog up brain cells, causing damage which ultimately results in cell death.

Flushing away the waste

In our brains, we need a way to clear away the waste protein which builds up throughout the day. Luckily, we have a built-in self-cleaning system, called the glymphatic system, which kicks in while we sleep.

The glymphatic system is a network of fluid-filled spaces and water channels that can carry this accumulated waste out of the brain. It uses cerebrospinal fluid, a clear liquid which surrounds the brain, to wash away the toxic proteins and dead cells that have built up during the day.

But in Parkinson’s and other neurodegenerative conditions such as Alzheimer’s, the system is not able to clear away the toxic clumps of alpha-synuclein effectively. So in 2019, alongside Alzheimer’s UK, we co-funded a project led by Ian to try and understand whether there are ways to boost this system. Read the previous blog where we interviewed Dr Ian Harrison.

The project involves studying mice that have been injected with alpha-synuclein. This injection triggers the alpha-synuclein already in the brain to start clumping together, which then starts to accumulate in the brain. As alpha-synuclein clumps form, they cause damage, and the clumps start to spread around other cells. This means that the mice start to develop some of the symptoms associated with Parkinson’s, such as movement problems.

To understand how the glymphatic system might be involved in the development of Parkinson’s symptoms, Ian has been using a drug which stops the system working. The drug targets a protein called aquaporin-4, which previous research has shown is important in making sure the glymphatic system works correctly.

Ian’s results so far show that when the mice are given this drug, they experience more problems with movement, and develop more clumps of alpha-synuclein in areas of the brain. This suggests that the glymphatic system is important in Parkinson’s. When it’s not working at all, the symptoms appear worse.

So is there a way to boost the glymphatic system?

Using the same mice, Ian is looking to address this question. This time, he’s using a different drug, which can speed up the glymphatic system. It does this by increasing the function of aquaporin-4. If it works, then he should see that the mice given this drug have fewer issues with movement, and fewer clumps of alpha-synuclein in their brain cells. This work is still ongoing, but Ian is excited to see where this will lead.

From mice to humans and back again

While using mice in research can be a really helpful tool to study what’s going on in the brain during Parkinson’s, it doesn’t quite tell us the whole story of what’s happening in humans. We need studies of human brains to understand the whole picture.

This is why Ian is working with Mark Lythgoe, Professor of Biomedical Imaging at University College London, to find out more about what’s happening in the brains of people with Parkinson’s.

Using tissue provided by the Parkinson’s UK Brain Bank, Ian and Mark are comparing areas of the brain in people who had early and late stage Parkinson’s, alongside people who didn’t have Parkinson’s.

They are looking for aquaporin-4, and for any clues that it might be linked to increases in alpha-synuclein build-up. When it’s working properly, aquaporin-4 should be found concentrated in one area of a particular type of brain cell. This helps it perform its main function: moving cerebrospinal fluid into the brain, so that the fluid can power the glymphatic system and clear away waste proteins. But when it’s not working properly, aquaporin-4 can be found spread throughout the cell, rather than concentrated to one area.

Looking at the brain tissue has helped Ian and Mark piece together more of the story that began by looking at the mice. In brain samples from people with late stages of Parkinson’s, there is less aquaporin-4 when compared to samples from people without Parkinson’s. And the aquaporin-4 that is there, isn’t where it should be. All this suggests the glymphatic system might not be working properly.

However, in people with early stages of Parkinson’s, there seems to be more aquaporin-4 than in people without Parkinson’s. This seems counterintuitive, but it could just mean that the body is trying harder to clear away the clumps of alpha-synuclein that have already started to form. By increasing aquaporin-4, the brain is trying to encourage the glymphatic system to work overtime, but unfortunately, this is not enough to clear away all the clumps of protein.

What’s the next stage?

Working with the Brain Bank tissue has helped Ian and Mark confirm some of what they are seeing in their experiments with mice. Studying brain tissue donated by people who have lived with Parkinson’s is invaluable to furthering our understanding of Parkinson’s. And finding potential new treatments.

As well as looking for aquaporin-4, Ian and Mark have also been able to take samples of alpha-synuclein from the Brain Bank tissue. This means that they have real protein from people with Parkinson’s, which can be used for further studies.

One of the ways they hope to use this is to further their work in mice. Using this alpha-synuclein, donated from people who had Parkinson’s, might help make the study more representative of what’s going on in humans, instead of relying on an artificial form of alpha-synuclein. They also hope to use these mice to work out the best time to give a treatment which would boost the glymphatic system, making it the most useful for people with Parkinson’s.

The work so far has shed light on how the glymphatic system might be involved in Parkinson’s, and ways that we might be able to harness its power to pave the way for new treatments to slow, or even stop, the progression of Parkinson’s.

With thanks to Dr Ian Harrison for his time and contributions to the article.