Lead Investigator: Dr John Boyle
Institution: University of Leeds
Grant type: Project grant
Duration: 3 years
Scientific Title: Hydrogen sulfide-mediated sulfhydration of the K+ channel Kv2.1: A new signalling pathway to target in the treatment of Alzheimer's disease
Why did we fund this project?
Comments from members of our Research Network:
'An interesting and as yet unexplored hypothesis.'
'Until there is prevention and cure, anything that can be used to treat/ameliorate dementia once it has been detected must be welcome.'
'Important and novel approach which is also applicable to wider brain science.'
What do we already know?
The build-up of plaques of amyloid-beta is a hallmark of Alzheimer's disease, and it is thought that it is amyloid-beta that is toxic to nerve cells, causing them to die, which leads to the symptoms of the disease.
Often when nerve cells die, it is through a process called apoptosis – a process of 'programmed cell death'. This happens when cells are exposed to things that are toxic, including amyloid-beta. One of the first things that happens when apoptosis begins is the generation of more pores in the outside of the cell called potassium channels.
Potassium is essential for the healthy functioning of nerve cells, and it enters and leaves the cell through these potassium channels. Normally, the amount of potassium in the cell is carefully controlled, but during apoptosis the appearance of lots more potassium channels causes lots of potassium to leave the cell.
Once this has happened, the cell cannot recover and so is destined to die. If this loss of potassium can be stopped, it may be possible to prevent toxic things, such as amyloid-beta, from killing nerve cells.
Nerve cells do have some defence mechanisms that can help to stop this from happening; one of these, the production of hydrogen sulfide, is the basis of this research project.
It is thought that hydrogen sulfide may protect against chemicals called 'free radicals' by acting as an antioxidant. Free radicals are thought to cause damage, especially in older age, and so may contribute to the damage to brain cells seen in Alzheimer's disease.
What does this project involve?
This research will investigate, in cells grown in the lab, the effect that amyloid-beta and hydrogen sulfide have on the health of the cells, paying particular attention to the potassium channels.
The researchers will use special techniques to measure the amount of potassium moving in and out of cells, to better understand how different conditions affect this. They will also measure, using different techniques, whether the amount of hydrogen sulfide and the number of potassium channels increases in the cells.
An additional set of experiments will measure memory in mice with genes that cause them to develop amyloid-beta plaques and exhibit symptoms of Alzheimer's disease. The researchers will test to see if treatment with hydrogen sulfide prevents these symptoms from developing.
How will this benefit people with dementia?
This research will build on our understanding of the underlying changes that occur within the brain during the development of Alzheimer's disease, and potential ways to prevent these from happening. Understanding these changes is essential in our progress towards developing better treatments for the condition.