Lead Investigator: Professor Simon Lovestone
Institution: University of Oxford
Grant type: Project, including a training fellowship.
Duration: 36 months
Scientific Title: Intelligence led drug discovery for the amyloid cascade; targeted informatics and the connectivity map of Alzheimer's disease
Why did we fund this project?
Comments from members of our Research Network:
'This is an important research topic, especially as the aims are a progression from previous studies.'
'This is an excellent proposal. Their work must continue to be funded by us.'
'Built on 15 years of research, this sounds positive - answers could be found that are important to further develop our understanding of Alzheimer's disease.'
What do we already know?
There are two main proteins that are associated with the development of Alzheimer's disease, which are called amyloid and tau. In Alzheimer's disease these two proteins form clumps that damage brain cells. However, it is so far unclear if and how these two proteins affect each other during disease development. Many attempts have been made to find treatments that prevent these proteins from damaging brain cells but so far none have been successful.
The lead investigator on this project, Prof Lovestone, was part of a team who discovered that the protein GSK3 can influence tau in a way that makes it harmful to neurons. Research by other groups showed that GSK3 can be controlled by another protein called Dkk1. With the help of Alzheimer's Society funding, Prof Lovestone and his colleagues have shown that the amyloid protein can influence the function of Dkk-1. They have undertaken several experiments that show that Dkk1 and GSK3 have an effect on the brain in both cell and animal models of Alzheimer's disease. Together, this data indicates that the Dkk1-GSK3 pathway could be a potential link between the two hallmarks of Alzheimer's disease, amyloid and tau.
What does this project involve?
The project intends to make use of a resource, developed in the US, which helps to find drugs that can influence how proteins work. This resource, called a Connectivity Map or cmap, allows researchers to analyse large amounts of data regarding how certain existing drugs affect the activity of proteins in cells grown in the lab.
The researchers intend to use this large resource to identify drugs that specifically affect the activity of their target genes. Once any suitable drugs are found, the researchers then intend to test their effects in cells in the lab and on rats that exhibit symptoms of Alzheimer's disease. If there are any treatments that are shown to be effective in these experiments then they could potentially be taken on to clinical trials in people.
How will this benefit people with dementia?
One of the key areas of research into Alzheimer's disease is finding a mechanism that will stop or slow the progression of the disease when targeted with a particular treatment.
Most drug developments so far have focused on targeting the amyloid protein. This project aims to find out whether there is another molecular pathway that can be used as a suitable target. An advantage of this project's approach is that the drugs used in the cmap screen have been previously developed, rather than having to create new drugs from scratch. This will allow any suitable drugs to be taken the next stages of development as soon as possible.