Lead Investigator: Professor Elizabeth Fisher
Institution: University College London
Grant type: PhD studentship
Duration: 3 years
Scientific Title: Finding new molecular pathways in Alzheimer's disease
Why did we fund this project?
Comments from members of our Research Network:
'I like this different approach looking at Down's syndrome sufferers and working back to identify the changes that may happen in the wider population/dementia patients.'
'Research to continue from experience and knowledge already achieved.'
'Dementia's interaction with other conditions and the causative effects need careful research.'
What do we already know?
People who have Down's syndrome have a greatly increased risk of developing Alzheimer's disease compared to the rest of the population. By studying Alzheimer's disease dementia in Down's syndrome, this will inform us about Alzheimer's disease in the rest of the population.
Chromosomes are very large molecules that lie in the centre of each of our cells and that carry the genes, or genetic information, that give instructions for how to make and maintain a human being. For most people, we inherit 23 chromosomes from our mother and 23 chromosomes from our father, so we have a set of 46 chromosomes in 23 pairs.
People with Down's syndrome have, for various possible reasons, an extra chromosome number 21. So Down's syndrome arises because people have three, not two, copies of all the genetic information on chromosome 21. In other words, they have an extra 'dose' of the genetic information from this chromosome.
The focus of this investigation is trying to understand the link between Alzheimer's disease and Down's syndrome. If the researchers can find the genes on human chromosome 21 that confer the greatly increased risk of early-onset Alzheimer's disease, then it is extremely likely these genes will be important in the rest of the population and, critically, they may provide new information for developing therapies for Alzheimer's disease.
A gene called the APP gene sits in the middle of human chromosome 21. It has been known for many years that mutations in this gene cause early-onset Alzheimer's disease. One type of naturally occurring (rare) mutation in the human population is families in whom the gene is present in two copies on one chromosome, so people actually have three copies of this gene (2 on one chromosome number 21 plus 1 on their other chromosome number 21). This tells us that having three 'doses' of APP gives rise to early-onset Alzheimer's disease, for unknown reasons.
People with Down's syndrome are in the same situation. They have three copies of human chromosome 21, therefore three copies of APP. That is almost certainly enough to explain the Alzheimer's disease many of them develop. However, the research team have shown this is not the whole story. There are other genes on human chromosome 21 that modulate the effects of APP.
It is extremely important for Alzheimer's disease research to find out what these other genes are, because if researchers can work out which genes on human chromosome 21 are important for modulating APP, they would be targets to help APP levels in everyone with Alzheimer's disease - they are potential targets for drugs to treat Alzheimer's disease.
What does this project involve?
The research team have a mouse model of Alzheimer's disease that develops the plaques found in human Alzheimer's disease, and they have a mouse model of Down's syndrome that, just like humans, carries an extra copy of human chromosome 21. The key finding in their lab within the last two years has been that they can show, in their mouse models, that when the chromosome 21 is present, this changes the Alzheimer's disease in the mouse model of Alzheimer's – for example, many more of the amyloid plaques develop and the mice also exhibit worse learning and memory.
The key question for this PhD studentship is: which gene(s) on human chromosome 21 are important for modulating the Alzheimer's disease mouse model?
The researchers will take their Alzheimer's disease mouse model and cross it to another type of mouse that has just a portion of the genes present on human chromosome 21. They will then start to prevent the a small number of genes from functioning that they believe are likely to be important for modulating the effects of APP in the Alzheimer's disease mouse model.
The researchers will look to see if reducing the function of individual genes changes the levels of APP protein back to normal in nerve cells taken from the mouse model. If they can identify important individual genes then this will be a critical piece of information for understanding what happens biochemical in nerve cells affected by Alzheimer's disease.
How will this benefit people with dementia?
This work is laboratory research that is fundamental for providing insight into the biochemistry of cells affected by Alzheimer's disease. The research team have made a specific particular finding through their work with mouse models of Alzheimer's disease and Down's syndrome and they now need to take this to next stage and identify the genes and molecules involved.
When they have done so, then they have targets for the development of new therapies for Alzheimer's disease. Ultimately, although translation from 'bench to bedside' takes many years, therapeutics depend on findings from basic research like this. This type of research offers long-term hope for ameliorating the effects of Alzheimer's disease and improving the quality of life for people affected by Alzheimer's disease.