Studying a protein interaction that increases accumulation of amyloid-beta

Read about a research project we funded into the characterisation of a novel APP interaction with holo-lactoferrin that facilitates Abeta production.

Lead applicant: Dr James Duce

Institution: University of Leeds

Grant type: PhD

Amount awarded: £84,834

Duration: 3 years

Why did we fund this project?

Comments from members of our Research Network:

'This project, building on previous work, seems worthy of support as I feel it has the potential to produce useful results.'

'In my view, this is much needed research - very relevant to people who have no pre-existing family history of the disease. A project that may offer hope for the design and development of improved and effective medications in the future.'

What do we already know?

Iron is essential for the normal function of the body but when this metal is not monitored and controlled by the cell it can be converted to a product that is potentially harmful to the body. It is the balance between getting rid of unwanted iron and retaining essential iron that is fundamental for keeping a healthy cell.

This research group previously discovered that a protein implicated in Alzheimer's disease called amyloid precursor protein (APP) prevents iron from reaching levels that damage the cell. For this role APP must remain on the surface of the cell but under certain conditions relevant to Alzheimer's, APP is cut in a way that not only causes iron retention but also produces another damaging product called amyloid-beta, which forms the plaques in the brain in Alzheimer's disease.

The researchers have now discovered that a protein called lactoferrin, which increases in response to inflammation, can attach to cell surface APP and promote APP cutting to produce amyloid-beta.

What does the project involve?

The student will use various techniques to investigate how lactoferrin can alter levels of iron and amyloid-beta as well as understand its significance in diseases such as Alzheimer's disease where inflammation may lead to iron and amyloid-beta accumulation. Experiments will range from studying how each protein on their own attaches to the other, through to how they work in individual cells and within a whole brain.

How will this benefit people with dementia?

This research will provide greater understanding in how inflammatory conditions that increase the presence of lactoferrin result in the damage to cells observed in Alzheimer's disease. By the student identifying the exact region within each protein that makes contact with the other protein, it is hoped that in the near future compounds can be sought to block this interaction. A drug that could stop the attachment of lactoferrin to APP could reduce the related iron and amyloid-beta toxicity.

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