Rising star Dr Ben Falcon at MRC LMB explores role of tau in dementia
They are normally present in our brain cells, helping them to maintain their function.
But when defective, tau proteins become our nemesis.
At the MRC Laboratory of Molecular Biology in Cambridge, scientists have been studying the role of tau in dementia. Postdoctoral researcher Dr Benjamin Falcon has been awarded the inaugural Rising Star Award by Alzheimer’s Research UK for his key role in the work.
“Tau normally exists on its own and helps to keep brain cells healthy,” he explains to the Cambridge Independent. “However, in disease it sticks together and forms very long filaments of many molecules. These are toxic to the cell and start to lead to cell death, which we call neurodegeneration.
“The clinical symptoms we see reflect the sites in the brain where tau filaments form. In Alzheimer’s disease, this is in parts of the brain associated with memory.”
Dr Falcon, working with research leaders Michel Goedert and Sjors Scheres, has determined the structure of tau filaments in three types of dementia – Alzheimer’s, the frontotemporal dementia Pick’s disease and, most recently, chronic traumatic encephalopathy (CTE).
“In each of these different diseases, we’ve found tau forms a different filament structure,” says Dr Falcon. “This could explain why different diseases develop, even though it is the same protein.
“The protein is a series of amino acids, like beads on a string. It is threaded in a certain way in Alzheimer’s to form broadly a C-shape. In Pick’s disease, it is more of a J-shape.
“These different shapes mean the filaments have completely different chemical and mechanical properties. This may have different functional consequences for how the protein behaves in the cell.”
CTE is a neurodegenerative disease associated with repetitive head impacts and has primarily been seen in those who have played contact sports like rugby, boxing and football, and in military veterans. Symptoms include behavioural changes, increased confusion and memory loss.
To study the structure of tau assemblies in this disease, Dr Falcon examined the brains of two ex-professional boxers and a former American football player using cryo-electron microscopy (cryo-EM) – a technique pioneered at the LMB by Richard Henderson, who shared the 2017 Nobel Prize in Chemistry for the work.
“CTE leads to tau aggregation in a very specific area of the brain, firstly around blood vessels, often in the cortical sulci [grooves in the brain].
“There wasn’t too much known about this disease. From the methods that were available, it looked very similar to tau in Alzheimer’s. It was a mystery as to why it wasn’t and, in fact, there were some around the world who thought it was Alzheimer’s and that it wasn’t caused by sport.
“Now we’ve seen that it has a unique structure that differs from the structure seen in Alzheimer’s and fronto-temporal dementia.
“It is the first clear neuropathological signature of this disease and shows that it is something in its own right. It is the only neurodegenerative disease we know of with a clear environmental cause.”
Dr Falcon found an extra molecule present within a cavity in the tau filaments of CTE patients, which is not present in those with Alzheimer’s or Pick’s diseases.
“The tau protein is wound around this central molecule, which suggests it is something that can cause the tau aggregation and might be linked to the environmental cause,” he says.
“The cavity is not present in the other diseases. We are trying to identify the molecule now and that might tell us a lot more about how CTE starts.
“We know what happens when the aggregates form: they spread and cause damage. But it is still completely unknown what leads them to aggregate in the first place.
“It is probably a very small percentage of people who have repetitive head impacts who go on to develop this disease.
“That could have something to do with the molecule developing in a subset of people. Perhaps they have elevated levels of this molecule, or some additional factors that favour the tau folding into these filaments.”
Understanding the structures of tau assemblies in Alzheimer’s, Pick’s disease and CTE could have significant implications for their future diagnosis and treatment.
Michel Goedert, who co-led the study on CTE, published in Nature this month, says: “The fact that the structures of the tau filaments were identical in the American football player and both boxers suggests that we’ve found unifying neuropathological criteria for the diagnosis of the disease.
“Our new knowledge of these structures could make it possible to definitively diagnose CTE in living patients by developing tracer compounds that will specifically bind to the tau fold of CTE.”
Dr Falcon adds: “There are a few first generation tracer compounds at present – drugs that bind to these filaments and can be tracked in the brain by PET scan.
“But it hasn’t been known why or how they bind to these filaments. They have been rather non-specific.
“So these structures will help us to figure out exactly how they are binding at the atomic level, which will help chemists to make them more specific, so we can have better diagnosis of these diseases.
“It may also help us to figure out how we could make a drug that binds to these filaments and stops them causing damage, or stops them forming in the first place
“We are now working on using the same technique of cryo-electron microscopy that we used to solve the structures of the filaments, but this time with candidate drugs bound to them.”
The research team used the cryo-EM facilities at the LMB, Diamond Light Source in Oxford – which is part-funded by the European Union – and the University of Leicester.
Dr Falcon received his award, including a grant to support his ongoing research, at the Alzheimer’s Research UK 2019 conference in Harrogate.
He says: “There is lots to do, which is why it is great to have the support of Alzheimer’s Research UK.”
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