Dr Helen Murray explores the relationship between repetitive head injuries and dementia. (A highlight from Auckland University’s Raising the Bar Home Edition)
From the discussion
During my PhD, I studied Alzheimer’s disease at the University of Auckland’s Centre for Brain Research. I worked with human tissue that was donated to the Neurological Foundation Human Brain Bank. And so throughout my PhD, I learnt how to preserve brain tissue and to prepare these ultra-thin slices of tissue for my studies, and how to apply very specific fluorescent labels that would bind to only one part of the tissue that I wanted to study. It could be something like a blood vessel, a certain type of brain cell, or one of the pathologies that we wanted to understand.
And throughout that process, I learnt how to study different processes within the brain tissue. I learnt how to take microscope images of the labelling that I was doing. These images enable us to look at what’s happening inside the brain at a microscopic level. Throughout the course of my PhD, I was studying Alzheimer’s disease and the main kind of character in the project I was looking at is this protein called Tau.
Tau’s normal function is to keep brain cells structurally stable, but in Alzheimer’s disease the Tau proteins become altered, and they start to clump together. And that causes them to form these dense structures called tangles.
These brain sections show unusual concentrations of theTau protein, shown here as brown spots. The more brown spots, the greater the brain damage. From L-R: A normal brain of a 65 year old, the brain of a football player, who suffered eight concussions and died aged 45; the brain of a 73 year old boxer who suffered from an extreme form of dementia pugilistica. Photo: WBUR Boston
Tangle pathology is not just a feature of Alzheimer’s, and CTE (chronic traumatic encephalopathy, a brain disease associated with traumatic concussion) is one of the diseases where we see this Tau protein start to form. But the difference between these diseases is where the Tau starts to accumulate in the brain, and how it moves round the brain, as the disease progresses.
In Alzheimer’s, we see these Tau tangles in the area of the brain that controls memory. That’s where they start to form first. But in CTE, we see the Tau tangles forming in the deep valleys between the folds in the brain, and more specifically round blood vessels. This pathology actually makes a lot of sense. When you get any kind of knock to the head, not necessarily a serious concussion, you get the forces that are concentrated around areas where the structure of the tissue is less consistent, around blood vessels and in these folds in the brain.
And so these Tau tangles are actually forming in areas of the brain which we know are experiencing the most stress. They start off in these valleys and then they start to move to other areas of the brain, including the parts that involve memory. It’s very different to what we see in Alzheimer’s disease. In the later stages of both diseases, however, the brain tissue can look quite similar.
To diagnose CTE in living people, we need to know what’s happening at the start of the disease. We want to know what is the tipping point when it starts to develop. There’s no magic number of [physical] hits to the brain that determine if someone will get CTE, and not everyone who plays a contact sport will get it. So why is it that some people do, and for them how do we modify, delay or stop this disease? The first step to answering any of these questions is to figure out what’s actually happening in the brain.
Painting the brain: an example of multiplex fluorescent labelling on human brain tissue illustrating (left to right) different types of brain cells, the highways of brain cell connections, and blood vessels on the same slice of tissue. Photo: Helen Murray, Centre for Brain Research, University of Auckland and Dragan Maric, National institutes of Health, USA.
When we study brain tissue we apply three or four fluorescent tags to see parts of the brain tissue. That number is because the microscopes we use can only separate three or four of these colours when we are taking the image. Because the brain is incredibly complex, we often have to mix and match these tags in different combinations, in different slices of brain tissue, so that we can see all the different things we would need to see in order to answer a question about the brain structure.
What we did at the NIH in the USA was to find a way to label the brain tissue with 100 different tags. All in one slice of brain tissue. We adjust the microscope so that we can make ten labels on the tissue at one time. Then we take that image and remove those labels, and add another ten. And so we build up this library of different tags on a single piece of brain tissue.
Now we have these incredible images which allow us to see all of the complex and fine detail that we would need to see in the brain tissue. So rather than just seeing one marker of a blood vessel, I can see all the different layers of that blood vessel, and to see if there is a specific part of that blood vessel that is changed. Now, we get at least 20 times as much information from a single piece of brain tissue than we would normally get.
More reading
To find out more about Dr Murray’s work on multiplex labelling, click on this link.
About the speaker
Photo: University of Auckland
Dr Helen Murray
Dr Helen Murray is a research fellow at the Centre for Brain Research at the University of Auckland and captain of the New Zealand women’s ice hockey team. Her research examines the cellular anatomy of the human brain and how it changes in neurodegenerative diseases, with a particular focus on dementia in contact sport athletes.
Raising the Bar is presented in association with the University of Auckland
Photo: University of Auckland
