Pioneering UK research reveals structure of key Alzheimer’s protein

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By Philip Tubby | Thursday 06 July 2017

Researchers in Cambridge have pioneered the use of advanced electron microscopes to detail the molecular structure of the hallmark Alzheimer’s disease protein, tau. The study, published today (Wednesday 5 July) in the journal Nature, reveals new insights into the properties of this key player in the development of Alzheimer’s and opens the door to new ways to study a host of degenerative brain diseases.

Diseases like Alzheimer’s involve the build-up of abnormally folded proteins that cause damage to nerve cells in the brain. The protein tau typically functions by helping nerve cells maintain their structure but in Alzheimer’s disease tau starts to behave abnormally and strands of tau protein, known as filaments, twist together to form tangles that are a characteristic feature of the disease.

The structure of a protein determines how it behaves and understanding the molecular formation of tau filaments is a key goal of researchers working to understand the processes involved in Alzheimer’s and to design drugs that could help the brain get rid of harmful tau tangles. The particular properties of tau filaments mean that standard techniques used to determine molecular structure haven’t yet been able to provide researchers with a detailed picture of its shape and composition.

In this study, researchers used a technique called cryo-EM (electron microscopy) that involves rapidly cooling a sample of protein to sub-zero temperatures. With the structure firmly fixed in place, scientists then bounce a stream of electrons off the sample to reveal its shape. The team used this method to analyse a sample of tau collected from the brain of a person who died with Alzheimer’s disease and donated her brain to research.

The technique allowed researchers to provide a detailed description of the structure of tau filaments, which will be important in understanding why they form in the brain and open up new avenues of research for scientists working on diseases that involve abnormally folded proteins.

Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:

“A build up of tau protein is a feature of a number of different degenerative brain diseases, and this work could help to answer key questions about why it starts to behave unusually and how it leads to such a wide variety of conditions. As well as improving our understanding of diseases like Alzheimer’s, knowing the precise structure of tau will help inform research into new treatments. Drugs that could clear away clumps of protein in the brain are a key goal for researchers, but to directly affect these proteins, molecules that make up a drug need to latch on and bind to their surface. Knowing the precise shape of these complex protein structures is enormously valuable in guiding the development of targeted drugs.

“Technological advances combined with the ingenuity of researchers like this team in Cambridge, are constantly pushing back the frontiers of our understanding of the diseases that cause dementia. The findings in this study represent an important step forward in the way we can study and understand proteins that are thought to be among the chief culprits in diseases like Alzheimer’s.”

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Philip Tubby