Drosophila as a model for Alzheimer s Disease

Alzheimer s Disease and other forms of senile dementia directly affect around 700,000 people in the UK at a cost of #17billion per annum. At present there is no cure for dementia and great efforts are being made to understand the disease and to find an effective treatment. Much of this research has been conducted in rats and mice. This has yielded important information about the changes within brain cells that lead to Alzheimer s Disease, but of course comes at a cost in terms of animal welfare. We propose to replace the use of animals in such studies with the fruit fly. Importantly, we can insert into the fruit fly human genes that produce proteins that we know are important for Alzheimer s Disease, like the protein tau. By using this simple model we can easily investigate the biochemical pathways that lead to the accumulation of tau and the damage that this causes. Moreover, we can administer to the fly chemicals to try and prevent this damage. These two benefits of this simple organism could lead to new targets for drugs, as well as new drugs themselves. In addition, studying the fruit fly may give better insight into the creation of appropriate animal models of Alzheimer s and other brain diseases, thereby reducing the number of animals required to develop accurate models of human disease.

Alzheimer s Disease (AD) is a progressive neurodegenerative disorder characterised by aggregations of extracellular beta-amyloid plaques and intracellular neurofibrillary tangles (NFT). The core constituent of NFTs is tau - a microtubule-associated protein -whose hyperphosphorylation results in pathogenic tangle formation. Accordingly there has been great interest in both the phosphorylation and aggregation of tau as targets for therapeutic intervention. Much of this work has been conducted in vertebrates, primarily rodents, and has required the generation of transgenic mice to model AD and other tau-related pathologies. As AD is a progressive condition it is often necessary to follow rodents for extended periods until some form of debilitation (cognitive, motor, sensory) is evident. This has obvious animal welfare issues and implications for the 3Rs, as have the many potentially redundant animal models that do not recapitulate the human disease. We suggest in this application an alternative to the use of vertebrates, primarily in target and drug discovery research.

We propose replacing vertebrates with the fruit fly Drosophila melanogaster to:
1) model basic aspects of the neurobiology of AD and other tauopathies, in particular the AMPK family of protein kinases, as proof of concept of being able to identify novel targets
2) use tau-dependent pathology in Drosophila as an assay for drugs targeting the phosphorylation cascade and tau aggregation

These studies are enormously facilitated by the ability to introduce into Drosophila human genes of interest - for example human tau. We have co-expressed tau with human kinases from the AMPK family. We have shown, for the first time, that one member, BRSK2, interacts with tau and worsens tau-dependent neurodegeneration of the fly eye. This is dependent on two upstream kinases, LKB1 and CaMKK. We now wish to explore 1) whether AMPK acts in the same way, 2) develop the fly as a model of human neurological disease and 3) use tau-mediated degeneration as an in vivo assay for drugs to prevent or reduce tau-dependent damage.

This work will address the 3Rs in several ways:
1) replacing vertebrates in routine and speculative assays
2) reducing the numbers of rodents required to generate transgenic models
3) refining relevant animal models of human disease