Defining how the balance of glial homeostasis and inflammation drives brain ageing and neurodegeneration to identify novel therapeutic targets

This project aims to enable development of novel therapies for age-related neurodegenerative diseases by prioritising and defining the molecular genetic mechanisms by which ageing leads to disease susceptibility. Ageing is the strongest risk factor for the costliest diseases in modern medicine, including Alzheimer’s disease (AD) and other neurodegenerative diseases for which there are currently no effective medicines and those in development are expensive and target one part of the underlying biology that leads to disease. We therefore need to define the mechanisms by which ageing affects the brain to find new targets for development of treatments that can delay development and progression of neurodegenerative diseases. Fully defining these mechanisms will require a multi-stage approach: (1) To define how the processes underlying ageing and neurodegenerative diseases interact, we need to identify the genes and gene networks that contribute to each process in human populations. (2) To move from these correlative studies to functional testing of these genes, we then need systematic methods to test the effects of their modulation in relevant cell types. (3) Finally, to determine how these genes act within an intact living nervous system, we need to test their action in a timely and cost-effective, short-lived whole-organism model system. This project will combine interdisciplinary and collaborative expertise in human population genomics, human glial and neuronal cell culture, genetic screening using the fruit fly Drosophila and bioinformatics to systematically address these challenges and uncover novel genes and pathways that modulate age-related neurodegenerative disease susceptibility. Our preliminary studies thus far have been very promising: our recently released work identified more than 100 genes that form a network of interactions and are associated with longevity from human Genome Wide Association Studies. These longevity-associated genes are significantly enriched in homeostatic processes of glial cells, which normally support neurons; and they are reduced with age, suggesting that disruption of normal glial function may be a significant factor in organism-wide ageing and disease. Moving forward from this work, we now propose a multi-pronged approach to prioritise this gene list and define the molecular mechanisms by which the most promising genes modulate brain ageing and neurodegenerative disease: (1) To enable medium-throughput screening approaches, we have selected a subset of these genes that present with the highest significance from our GWAS-generated list from human data and are well expressed in microglia and astrocytes. (2) We will use cultured human microglia and astrocytes to define how reduced expression of each gene influences glial homeostatic balance in response to cytotoxic inflammatory and AD-model conditions. (3) In parallel, we will use Drosophila models of Alzheimer’s-associated toxicity and normal ageing to define how each gene modulates ageing and disease susceptibility in a whole organism. Ultimately, this project will uncover a new set of genes, pathways and molecular mechanisms that will form the basis of our next projects, where we will collaborate with researchers using mammalian models and drug discovery platforms to validate their importance as targets for new disease-altering medicines for AD or as biomarkers of functional ageing of the brain prior to disease onset. Thus our work has potential for application not only to AD, but more widely to age-related neurodegenerative diseases in future.