From genetics to the cellular phase of Alzheimer’s disease: untangling the role of lipid pathways in microglia responses to amyloid pathology

Microglia are critically involved in complex neurological disorders with a strong genetic component, such as Alzheimer’s disease, Parkinson's disease and Frontotemporal dementia. While mouse microglia can recapitulate aspects of human microglia physiology, they do not fully capture the human genetic aspects of disease nor reproduce all human cell states. However, primary cultures of human microglia or microglia derived from human pluripotent stem cells (PSC) are difficult to maintain in brain-relevant cell states in vitro. To address these hurdles we described MIGRATE (Microglia In vitro Generation Refined for Advanced Transplantation Experiments), a combined in vitro differentiation and in vivo xenotransplantation protocol to study human microglia in the context of the mouse brain. We demonstrated that the transplanted cells recapitulate transcriptionally human primary microglia ex vivo, are capable to react to challenges and show expression of human-specific Alzheimer’s disease risk genes. In this PhD thesis we aimed to use MIGRATE to describe the heterogenous response of human microglia to amyloid pathology, to characterize the microglia progenitor population capable to colonize the in vivo brain environment, and to set up a platform for in vivo genetic perturbation screenings in single microglia cells. We anticipate that MIGRATE coupled to genetic manipulations and multi-omics approaches could address a variety of questions concerning normal physiology, development and pathology of human microglia in the in vivo environment of the brain.