The kaleidoscope of microglia phenotypes: Microglia transcriptional phenotypes from development to disease

Microglia are relatively long-lived and self-sustainable macrophages of the central nervous system (CNS). Microglia functions exceed the non-specific defense functions classically associated with the innate immune system and their main function is to maintain CNS homeostasis. In recent years, gene expression profiling technology has progressed rapidly and now allows for the detection of the transcriptome and epigenome of single cells. The main aims of this dissertation were 1) to identify and characterize transcriptional phenotypes of microglia subtypes in human development and Alzheimer’s disease, 2) to reveal how postnatal stress affects microglia development and functions in adulthood, and 3) how epigenetic mechanisms control microglia transcriptional phenotypes. In chapter 2, it is shown that human microglia transition from activated towards mature cells during the early second trimester of gestation and likely exhibit (partial) immune-sensing properties. In chapter 3, it is described that early-life stress changes the microglia transcriptome in adult mice and affects microglia development and responsiveness to an immune challenge with LPS. In chapter 4, it was identified that the transcriptomes of microglia acutely isolated from post mortem control and Alzheimer’s disease CNS tissue do not differ. This finding is likely caused by technical limitations, rather than the underlying biology. In chapter 5, transcriptomic and epigenetic profiles of tolerant and trained microglia and transcription factor networks driving these phenotypes were identified. Overall, this thesis illustrates the transcriptional heterogeneity and specificity of microglia during the human and mouse lifespan.