Induced pluripotent stem cell-derived microglia as a model for Alzheimer’s disease (360G-Wellcome-105219_Z_14_Z)

The role of microglia in Alzheimer’s disease pathogenesis is still controversial. Activated microglia are found to be associated with amyloid plaques in brains of AD patients and in mouse models. They may play a neuroprotective role by secreting proteolytic enzymes that degrade Abeta and expressing receptors involved in its clearance and phagocytosis. However, microglia might also contribute to disease progression through production of inflammatory mediators. Despite the recognised importance for research into the role of microglia in AD, there is currently an unmet need for human cell models that enable in-depth mechanistic studies. One route to the development of highly informative cell models is the differentiation of human patient-derived iPS cells, which intrinsically incorporate human genetics and bridge the gap between clinical AD and animal models. This project will develop AD microglial models by building on work that has established a standardised protocol for the derivation of microglia from human iPSCs. The project will be structured to firstly gain an in-depth characterisation of iPSC-derived microglia. Secondly, the iPSC-derived microglial model will be validated against anticipated microglial phenotypes. Finally, once established, the model will be used to investigate the role of AD risk genes in aspects of microglial biology.