How do cells make and use energy during Alzheimer's disease?

Research project: Novel consequences of mitochondrial beta-amyloid in Alzheimer's disease.

Lead Investigator: Professor Frank Gunn-Moore
Institution: University of St Andrews
Grant type: PhD studentship
Duration: 3 years
Amount: £75,000

What do we already know?

As we age, the energy sources that our brains use change. In particular, when young, our brains exclusively use glucose as an energy source; however, as we age our brains have to use a range of other molecules to create this energy. In Alzheimer's disease there is an accelerated change in how our brains use different energy sources, with a decrease in glucose use, which is what is measured by a type of brain scan called a Positron Emission Tomography (PET) scan.

All cells within the body, including brain cells, contain parts called mitochondria. Mitochondria are the 'power houses' of cells and use make all of the energy that cells, need to function properly. As brains age, the mitochondria of brain cells start to use lipids and fats to generate energy, instead of using glucose - a protein called ABAD has been shown to be important in this process.

Previous work by these researchers has found that amyloid clumps, or 'plaques', which are a hallmark of Alzheimer's disease, interfere with ABAD, and so affect the ability of the mitochondria to produce energy in older brains. When amyloid sticks to ABAD, it changes its activation and has been shown to cause different genes to become 'switched on'; this results in different functioning and behaviour of the brain. Preventing amyloid from interfering with the ABAD has been shown to reverse these changes.

The researchers have also found that another protein, cyclophilin D, also interacts with ABAD, potentially altering its level of activity. Therefore, the researchers have uncovered a brand new process that may be involved in the development of Alzheimer's disease.

What does this project involve?

The researchers will conduct work to investigate how ABAD is affected by amyloid and how this can be altered to provide therapies for Alzheimer's disease. Understanding these processes more clearly will also help us to understand more about the underlying changes that occur during Alzheimer's disease.

Additionally, the researchers will conduct experiments to see how ABAD and cyclophilin D interact, and how this interaction is affected in Alzheimer's disease.

This project will also allow the researchers to assess a novel drug therapy that they are developing, to see how this drug works in relation to ABAD.

How will this benefit people with dementia?

This project will allow the researchers to work towards developing potential therapies to help the brain to continue using glucose as its energy source, rather than switch to other, less efficient sources, which can result in the deterioration of brain cell function seen in Alzheimer's disease.

Developing treatments that could target this as soon as it is discovered could allow brain cells to be more resistant to other changes within the brain during Alzheimer's disease (such as the build-up of the proteins amyloid and tau, which are hallmarks of the disease).

The results from this project will also give us further understanding of some of the changes that occur during Alzheimer's disease, allowing us to build a more comprehensive picture of the disease.