Evaluation of the kinases responsible for tau toxicity

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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.