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.
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