IMPC: Characterisation a novel Alzheimer's disease susceptibility locus

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It would be of great assistance in the design of new drugs for Alzheimer's disease (AD) and other dementias if the biological mechanisms that make some people and not others susceptible to these diseases were understood better. This would assist drug companies to choose the best targets when they design new drugs and enable them to trial drugs that already exist but whose use is not obviously indicated in the treatment of AD. Many new genes that are associated with increased susceptibility to AD and other dementias have been implicated recently through big genetic studies, but in most cases it is not clear how these genes influence disease. One of the problems is that the genetic variants detected mostly do not have an obvious biological function. In our recent studies we have detected a number of variants predicted to have direct biological effects on proteins, which we can test experimentally. One such variant is in a little studied gene called ABI3. We are interested in the protein produced by ABI3 because it is also part of a network of proteins that we have previously identified as being critical in AD pathogenesis and it is expressed at high levels in microglia, an immune cell of the brain. In this proposal we will test the hypothesis that ABI3 regulates microglia functions that contribute to the development of AD; we expect that understanding the pathways controlled by ABI3 will provide novel insight into the mechanisms underlying the development of AD. We will use recently generated Abi3-deficient mice to determine the key functions of the Abi3 protein in the first steps to understanding its contribution to disease susceptibility in AD.