Investigating the biological role of the Alzheimer’s disease risk gene APOE

Lead Investigator: Prof Seth Love

Institution: University of Bristol

Grant type: Project Grant

Duration: 36 months

Amount: £223,780

Scientific Title: The dynamic role of astrocyte secreted APOΕ4 in Alzheimer's disease: investigations using human induced pluripotent stem cells 

Why did we fund this project?

Comments from members of our Research Network:

'Clear and convincing rationale and explanation, exemplary experience and resources at the frontiers of knowledge, research with practical potential'

'An important project that is able to use an existing cancer drug on human nerve cells'

'I found this proposal of great interest and potentially of great value'

What do we already know?

The most common form of Alzheimer's disease has a number of risk factors, including genetic ones. The gene that is associated with the strongest risk of developing Alzheimer's disease is called APOE. This gene has several variations, called APOE2, 3 and 4. Variant 4 is associated with an increased risk of Alzheimer's disease; variant 2 has been shown to reduce the risk.

The exact role that APOE plays in Alzheimer's disease development is currently unclear. Researchers do know that the APOE protein takes fats called lipids to parts of the brain where they are required to keep the brain working well. In Alzheimer's disease, the brain becomes overloaded with toxic clumps of a protein called amyloid, which causes the nerve cells to stop functioning properly and eventually to die. In addition to helping nerve cells to function, research indicates that APOE may have an important role in removing these clumps from the brain.

Nerve cells also depend on another type of brain cell, called an astrocyte, which helps to mop up substances that damage nerve cells and help them to repair themselves. Another way that astrocytes help keep the brain healthy is through the production of APOE.

Scientists have recently found that diseases of the brain, such as Alzheimer's, can be exacerbated by problems with the astrocytes that impair their ability to perform these functions. 

What does this project involve?

Most of the research that has been conducted into the role of APOE so far has used rodents. Professor Love and his colleagues intend to make use of an exciting technological breakthrough, called induced Pluriopotent Stem Cells (iPSCs), to investigate the role of APOE in brain cells. The reason that iPSCs are so important to research is because they are cells that are taken from people and can be reprogrammed to form any other cell type in the body. Professor Love has collected skin samples from people with and without Alzheimer's disease and tested them to find out which variant of APOE is present in the cells. These skin cells have been reprogrammed into nerve cells or astrocytes.

The researchers will use these specialised cells to determine how the different variants of APOE behave in brain cells. This includes finding out how the different APOE types affect the ability of nerve cells and astrocytes to interact with each other. They will also investigate whether the different APOE types can affect the response of nerve cells and astrocytes to the toxic amyloid clumps.

The study will also investigate whether an existing drug that targets APOE, called Bexarotene, can have an effect on these reprogrammed brain cells and reduce the problems associated with Alzheimer's disease. 

How will this benefit people with dementia?

Understanding the exact role of APOE in Alzheimer's disease development will help to shed light on exactly why this gene is associated with the condition. Using cells that come from human volunteers will allow researchers to understand the changes that occur in people.

If the researchers can understand the role of APOE then it may open the door to finding new pathways or mechanisms to target with potential therapies. As Bexarotene is already approved for use in cancer, if it is shown to be effective in human nerve cells it could be entered into clinical trials faster than with newly developed drugs. This is an example of drug repurposing, a key part of our Drug Discovery programme.