Abstract

Microglia are the resident immune cells of the brain. In Alzheimer’s disease, microglia are a major gatekeeper controlling both onset and progression. The exact ways in which malfunctioning microglia contribute to disease is not well understood. This is especially so when we ask how microglia affect the brain circuits controlling memory and thinking. Big data enables fast access to new potential targets and models for these events, but these ideas need to be tested in experimental systems to be able to discern fact from fiction. We first selected candidate novel regulators controlling microglia in disease by studying human brain tissue at single cell resolution, followed by high-throughput genetic screens in human stem cell-derived microglia. This project follows these hits by incorporating them into a novel human stem model of human brain circuitry. We will determine which molecular regulators control the good vs. bad of microglia based on outcomes related to impaired brain circuitry in disease. By combining primary human brain data and human cell models, this work seeks to accelerate our ability to discover and test novel drug targets impacting cognitive decline in dementia that are fully anchored in human genetics and human biology.