In vivo modelling of human microglial alterations associated with Alzheimer's disease polygenic risk

Genome wide association studies have identified multiple genetic variants that are associated with increased risk of developing Alzheimer's disease (AD). Strikingly, bio-statistical analysis of risk loci most strongly implicates innate immunity and microglia function as target pathways involved in AD etiology. Moreover, novel statistical approaches allow polygenic risk scores for AD to be assigned, with a predictive accuracy for individuals at highest and lowest risk of over 90%. To understand the impact of polygenic risk genotype on mechanisms of AD onset and progression this project will establish novel microglial models from induced pluripotent stem cells (IPSC) derived from individuals in patient cohorts identified at the extremes of polygenic risk of AD. IPSCs will be differentiated into microglia. High and low AD risk IPSCmicroglia will be compared using multiple functional assays e.g. pro- and anti-inflammatory responses to beta-amyloid and cell stress stimuli, cell migration and phagocytosis. Assays will focus on high-content live cell imaging and be developed with a view to rapid translation of work for drug screening and testing with industrial partners. To investigate microglial behavior in vivo and the homeostatic role played in brains of wildtype and transgenic AD model mice, microglial cell transplantation will be used to establish novel human <-> mouse chimeric models. T