New human brain membrane discovered

By
Henrik Larsen
The brain membranes

Danish and American researchers have identified a previously unknown brain structure. The super-thin membrane, just one cell thick, forms part of the brain’s immune system.

Kjeld Møllgård, Professor of Neuroanatomy at the Panum Institute, University of Copenhagen (UCPH), has taught thousands of Danish medical students about the structure of the brain.

He spent more than half a century telling them, ‘We have three brain membranes – dura, arachnoid and pia.’ When he realised a couple of years ago that this was not the full picture, it was an experience he will never forget.

Møllgård, who turned 80 last autumn, was sitting in his office at the Panum Institute that day, studying advanced microscope images of mammal brains.

Keld Møllgard
Kjeld Møllgård, Professor of Neuroanatomy at the Panum Institute, University of Copenhagen (UCPH), discovered the previously unknown brain membrane on a microscope image. Møllgård is a professor of neuroanatomy. Møllgård was the Rector of UCPH from 1994 to 2002.

The brains were from genetically engineered and euthanised mice. Their heads had been removed and then sliced from ear to ear into ultra-thin sections. It may sound elaborate, but the idea was to preserve all of the associated brain structures, not just dissect the brain. It turned out to be a wise strategy.

Although Møllgård was actually looking for lymphatic vessels in the brain – which would be highlighted by particular colouring agents that bind to these tissues – he suddenly realised that the image also revealed a very delicate, hitherto unknown membrane.

Further studies identified it as a fourth brain membrane. Subsequent analyses confirmed that this membrane, now officially named SLYM, also exists in humans.

Science, one of the world’s foremost scientific journals, recently published an article about the research.

The professor describes the discovery of SLYM as the ‘most important achievement’ of his long research career, adding that he finds it ‘quite funny that it happened at my age’.

 

Brainwashing

The genetically engineered mice Professor Møllgård studied were given to him by another brain researcher – Professor Maiken Nedergaard of the Center for Translational Neuromedicine at UCPH and the University of Rochester in the USA.

For a number of years, the Lundbeck Foundation has been helping to fund Nedergaard’s research into the glymphatic system – popularly known as the ‘brain’s dishwasher’. In humans and other mammals, this biological system, comprising a complex network of vessels, ensures that the brain is continuously cleaned to expel harmful waste products like degraded proteins.

Most of the process occurs while we are asleep, when the brain opens its internal doors, gates and pathways and allows cerebrospinal fluid (CSF) to flow through. We produce around 500 ml of CSF a day. As it drains out of the brain via veins, nerves and lymphatic vessels, waste products are flushed out with it – much like a house discharges wastewater into drains.

Maiken Nedergaard
Maiken Nedergaard is a professor at the Center for Translational Neuromedicine at the University of Copenhagen and the University of Rochester in the US. She headed the international research team that in 2013 demonstrated the existence of the glymphatic system – the ‘brain’s dishwasher’ – which keeps the brain free of harmful waste products. SLYM – the newly discovered brain membrane – also appears to play a crucial role in this process.

Nedergaard was head of the international research team that announced the existence of the glymphatic system in 2013. Since then, she has been researching how it works, including mapping the brain’s plumbing in greater detail and how the system lets in clean CSF and expels the dirty variety without the two mixing.

According to Nedergaard, it is crucial to understand the anatomy of the brain-lymphatic vessels in order to conduct this mapping exercise.

‘And it’s not easy. For example, previous experiments on mice showed mammals have lymphatic vessels that connect the brain straight to the skull. So, when you remove a mouse brain from the skull to study it, you destroy those vessels. That’s why I asked Professor Møllgård, an authority on neuroanatomy – especially brain membranes and barriers – to help me analyse mouse brains by removing whole heads from genetically engineered mice and slicing them into very thin sections – complete with skin, hair, teeth, bones and brains – the lot!

He agreed and not only identified lymphatic vessels in the samples but also a previously unknown fourth membrane, SLYM, which is amazing! The discovery is remarkable, not just because parts of the textbooks on neuroanatomy now need to be fundamentally revised – which is isn’t exactly an everyday occurrence – but also because studying the previously unknown membrane will help us develop a new understanding of things like Alzheimer’s and other neurological disorders,’ Nedergaard explains.

 

Documenting the discovery

The four brain membranes – pia, SLYM, arachnoid and dura – combine to form a protective barrier system that encases the human brain and keeps it bathed in cerebrospinal fluid (CSF).

Professor Møllgård discovered the fourth membrane, SLYM, in the cavity between the pia and the arachnoid. The structure visible in the microscope image was unmistakably a membrane, but it took a great deal of in-depth investigation to establish this with scientific certainty. It was also important to explore the functions of SLYM. All of this took time.

Møllgård, Nedergaard and researchers at the universities of Copenhagen and Rochester worked closely together on these studies and then wrote the Science article.

As well as documenting the existence of the fourth membrane, the article identifies SLYM’s characteristic properties, including its role in the brain’s immune system. For example, the Danish and American researchers discovered that it contains special immune cells that monitor whether anything is wrong in the brain.

The cells do part of this monitoring by continuously scanning the cerebrospinal fluid for signs of infection or cell damage and activating the immune system when needed. Nedergaard’s laboratory performed cell experiments to measure this, provoking SLYM by introducing infections and inflicting mechanical damage. These experiments also showed that the fourth membrane weakens and may leak as its cells age.

Another characteristic property of SLYM is its role in cerebrospinal fluid (CSF) circulation. Nedergaard’s laboratory showed that SLYM can direct the movements of the fluid – and also appears to play a crucial role in keeping clean and dirty CSF apart.

‘These two properties will now be explored in greater depth to generate new insights into Alzheimer’s and other neurodegenerative disorders. It is a logical next step to investigate this because good CSF circulation and efficient disposal of degraded proteins and other waste products are vital for keeping the brain healthy,’ Nedergaard says.

‘With Alzheimer’s, for example, degraded proteins build up which otherwise ought to have been flushed out of the brain. So, finding out more about how SLYM works may enhance our understanding of neurodegenerative disorders and improve our chances of developing new forms of treatment for them.’

The fourth membrane discovered by Professor Kjeld Møllgård has been officially named SLYM, an abbreviation for Subarachnoidal LYmphatic-like Membrane.

 

 

Hjernehinder -  Illustration
The brain membranes. ​​​Illustration: Dan Xue

The brain membranes

These illustrations show the four mammalian brain membranes in mice and humans: Dura, arachnoid, SLYM and pia.

SLYM – the newly discovered fourth membrane – is shown in green.

The four illustrations show what happens if you remove a brain from the skull before examining it.

Inevitably, this will rip the SLYM and other brain structures apart – as shown top right – rendering it impossible to find these structures intact and study them.

SLYM was only discovered when Professor Kjeld Møllgård removed whole mice heads and sliced them into ultra-thin sections from ear to ear – complete with skin, hair, teeth, bones and everything else.

It was in these sections that he identified SLYM.

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