Investigating whether a particular type of amyloid protein is linked to Alzheimer’s disease development

Read about a research project we funded into pyroglutamylated amyloid-β in Alzheimer's and Lewy body disease.

Lead Investigator: Professor Johannes Attems
Institution: Newcastle University
Grant type: Project
Duration: 36 months
Amount:  £259,909

Why did we fund this project?

Comments from members of our Research Network:

'A really exciting piece of research that has the potential to hugely impact on diagnosis and therapy'

'This appears to offer the prospect of establishing some basic principles for further research'

'Just reading this makes me aware of what a mammoth task confronts researchers. It is a very thorough application'

What do we already know?

Many forms of dementia are characterised by the presence of toxic clumps of protein in the brain. In Alzheimer's disease, these clumps are formed of proteins called amyloid and tau. In dementia with Lewy bodies, these clumps are made from a protein called alpha-synuclein. 

One of the leading theories behind the development of Alzheimer's disease is that amyloid forms clumps first, and these cause tau to form the toxic tangles associated with the condition. However, examining the brains of older people has shown that some people have the toxic amyloid in their brains but not tau. Others have tau clumps but not amyloid. These people often do not have symptoms of Alzheimer's disease. This could mean that amyloid is not the cause of tau tangling. Another theory is that it is only certain types of amyloid that cause tau to form tangles. 

Amyloid can be present in several forms. One of these forms is called pyroglutamylated amyloid. Previous work in animals has shown that pyroglutamylated amyloid is linked to the creation of toxic tau tangles. 

What does this project involve?

The researchers will use tissues from brains of people who had Alzheimer's disease and those who did not. They will examine whether pyroglutamylated amyloid is present more often in the brains of people who had Alzheimer's disease. They will use cutting-edge techniques that can accurately measure the levels of this type of amyloid in the brain. 

The researchers are also aiming to examine the brains of people who had dementia with Lewy bodies, to find out whether pyroglutamylated amyloid also affects the formation of the alpha-synuclein clumps. 

They will use this data to better understand the relationship between amyloid and tau, and between amyloid and alpha-synuclein. They will find out whether pyroglutmylated amyloid is related to symptoms of dementia and identify whether it is a likely cause of damage to brain cells. They will also use spinal fluid measurements to see if pyroglutamylated amyloid is present in the fluid, which could be a useful tool for diagnosis.

How will this benefit people with dementia?

Amyloid and tau are two major hallmarks of Alzheimer's disease, but the way that they affect each other is largely unknown. This project will further our understanding of how these two proteins work in the brain, and how this contributes towards Alzheimer's disease. The researchers also hope to make similar clarifications for the role of amyloid and alpha-synuclein in dementia with Lewy bodies. 

By understanding more about the role of this type of amyloid, the researchers can understand if detecting this form of the protein can help in more accurately diagnosing the condition. This could help to ensure that people are able to access the support, treatments and information that they need as soon as possible. 

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