Investigating the interactions that cause tau to form tangles in Alzheimer's disease

Lead Investigator: Dr Richard Wade-Martins
Institution: University of Oxford
Grant type: Project
Duration: 36 months
Amount: £223,092
Scientific Title: Mechanisms underlying the tau protein-mediated effects of amyloid beta on synaptic plasticity

Why did we fund this project?

Comments from members of our Research Network:

'I believe this to be important work because it builds upon previous work in understanding some of the earliest parts of the process in the development of Alzheimer's disease.'

'Researching causes in early stages has to be of higher priority.'

'This sounds like a progressive research programme and worthwhile for future medication purposes.'

What do we already know?

Alzheimer's disease results from the build-up of of two proteins in the brain; toxic tangles inside of the cell and amyloid plaques outside of it.

The leading hypothesis for the explanation of the relationship between these two proteins is called the amyloid hypothesis. It suggests that amyloid accumulation comes first, as a result of the inability of the blood flow to clear the amyloid fast enough. This build up, forming amyloid plaqyes, then triggers tau accumulation, which disrupts the functioning of neurones and eventually leads to their death.

Dr Wade-Martins previously showed that without the presence of tau, amyloid build up does no affect brain cell function. The researchers also showed that by blocking the interaction between amyloid and tau, extra molecules of phosphate (which cause the tau to break down and form tangles) did not attach.

Understanding the mechanisms involved in the attachment of these molecules will help researchers to better understand what happens when tau breaks down, and how to prevent the amyloid from signalling for this to happen.

What does this project involve?

This project will involve studying a mouse model that produces the normal or an abnormal version of human tau rather than the mouse version of tau. This model will be used to investigate the different interactions with amyloid of the normal and mutated human tau, so helping the researchers to understand the components that are important for this interaction. The effects of amyloid and tau on the 'firing' of nerve cells, the effectiveness of which is thought to relate to the ability to form memories, will be investigated.

The researchers will also use human brain cells grown in the laboratory, with the use of stem cells developed from skin samples. Using cutting-edge technology to 'delete' the gene that is responsible for the production of the tau protein to investigate the effects of this, and whether they are the same as seen in the mouse model - this has never been done before.

How will this benefit people with dementia?

This project seeks to understand critical aspects of the interaction between amyloid and tau proteins in Alzheimer's disease. This interaction is critical to brain cell dysfunction, memory impairment and cognitive decline. Understanding the interaction is an important and necessary step in the search for a treatment and cure for Alzheimer's disease.

Once we understand the interaction, we will be better placed to design novel therapeutic approaches to prevent or modify it.