Microglia: Development of a human in vitro model, analysis of motility and effects of phagocytosis in the hippocampal neurogenic niche

Abstract

This PhD Thesis discusses several topics related to microglia, the resident macrophages of the brain parenchyma. They are derived from yolk sack primitive macrophages that colonize the brain early during embryonic development. Microglia contribute to the correct development and functioning of the central nervous system with their multiple functions, including their role as phagocytes clearing the brain parenchyma from apoptotic cells and protein aggregates. Microglia are also involved in most neurological and neurodegenerative diseases, especially since genome-wide association studies have found that many microglia-specific genes are significant risk factors for neurodegenerative diseases. This PhD Thesis focusses on two aspects of microglial physiology. First, on the development of human models of microglia and their importance in the use of microglia as a therapeutic target in neurodegenerative diseases. Finally, on microglial process motility and phagocytosis, two essential functions of homeostatic microglia that can become compromised in pathology. This thesis defines a method for the semi-automated analysis of microglia in 3D and how inflammation affects microglial motility. This thesis also shows how an impairment of phagocytosis in the adult neurogenic niche negatively affects the neurogenic cascade suggesting a crosstalk between microglia and neural progenitor cells.