Evaluation of the kinases responsible for tau toxicity

Neurodegenerative diseases such as Alzheimer?s disease are extremely debilitating and distressing. As Alzheimer?s disease mainly affects older people and the current demographic trend is towards a population that continues to live longer the impact of Alzheimer?s will increase significantly. To allow more effective treatments to be developed more needs to be understood about the underlying causes of the disease. It is currently recognised that there is an abnormal build-up of protein in the brain cells of Alzheimer?s sufferers which results in the loss of nerve cells which leads ultimately to dementia. Much work has previously established that a protein known as tau is one of the proteins that accumulates in diseased cells. Tau normally has an important role for nerve cell function but in Alzheimer?s disease this protein begins to function abnormally. In the disease state the tau protein that builds up is chemically altered by the abnormal addition of excess amounts of phosphate. One hope for the development of treatments for Alzheimer?s disease is to find drugs that block the enzymes (known as kinases) that add this phosphate onto the tau protein. Several candidate kinases have been identified and we now need to identify which of the kinases is a major contributor to the formation of toxic tau protein in diseased cells. It is not possible to do this in human and is also difficult to do rapidly in mouse. In this project we will use the fruit fly (Drosophila) as a model system where we can accurately and efficiently evaluate which of the kinases are responsible for the production of abnormally phosphorylated tau. By identifying the kinases that are responsible we will enable the development of more effective therapies. We also plan to investigate whether we can use Drosophila as an assay system to test the effectiveness of drugs that may alleviate the causes of Alzheimer?s disease. As the work that we plan to do may have significant implications for the future treatment of a well known disease we will endeavour to make the results of our work available to the general public by presenting significant advances on our website, through peer-reviewed publications and where appropriate through press announcements.

Alzheimer?s disease (AD) affects 750,000 people in the UK alone and the trend is for this number to increase. This creates a considerable burden on the affected individuals, their families and society in general both in terms of the suffering involved but also the significant economic cost. Current drugs are efficient at tackling the symptoms of the disease but less efficient at tackling the underlying neurodegeneration. As such there is an urgent need to identify new drug targets and therapies. Tau hyperphosphorylation plays a critical role in the disease pathology. We have obtained recent evidence that a small number of kinases are responsible for the majority of the phosphorylation sites on tau in AD brain. Here we propose to use the Drosophila model system as a whole animal assay to investigate which of these kinases and the sites they phosphorylate are responsible for the generation of toxic forms of tau in vivo. We further propose to investigate whether the Drosophila model can be used as a high throughput assay to identify molecules that prevent the neurodegenerative process in AD.