Down Syndrome and Alzheimer's Disease - determining which chromosome 21 gene or genes when over-expressed modulate Abeta toxicity and accumulation

Down Syndrome (DS) is the greatest risk factor for early-onset Alzheimer's disease (AD). Over the last decades, greater longevity of people with DS has increased the burden of AD in this population. People with DS carry an extra copy of chromosome 21 (Hsa21), which encodes 234 genes including APP. The gene product of APP is cleaved into amyloid-beta (Ab), which aggregates in the brain to form amyloid plaques, characteristic of early AD. Duplication of APP alone has been shown to be sufficient to cause early-onset AD, suggesting a crucial role of this gene in increasing the risk of AD for people with DS. However, the contribution of other Hsa21 gene duplications to AD risk is not yet understood. Wiseman et al., recently demonstrated that the triplication of HSa21 genes other than APPincreases the risk of AD pathology in mouse models. Specifically, a region of 39 Hsa21 orthologues was found to be sufficient to exacerbate Ab aggregation and cognitive decline in mice. In this project, I want to identify and characterise the Hsa21 gene(s) responsible for the observed increase in AD risk as a result of their trisomy. In line with NC3Rs' principles of reducing, replacing and refining the use of animals in research, I will be investigating our research question using the fruit fly Drosophila melanogaster, replacing the need for mouse models. This will allow me to over-express each of the candidate gene in turn to assess their effects on Abtoxicity and accumulation in the fly brain. In addition, I aim to determine the the clinical relevance of the genes identified by using human genetic and clinical data sets collected by the LonDownS consortium and neuropathological studies of post-mortem brain material. This research will further our understanding of AD pathology in the context of DS and may contribute to the development of novel therapies for people with early-onset AD.