Microglia shapes and states: Exploring microglia's path from homeostasis to disease

Microglia are immune cells in the central nervous system responsible for maintaining brain health and homeostasis. They constantly monitor their surroundings for danger signals and can become reactive, changing their shape and releasing inflammatory molecules when they detect threats. One of their important functions is phagocytosis, which involves clearing apoptotic cells, debris, and pathogens. Dysregulation of microglial functions is linked to aging and neurodegenerative diseases. With age, microglia become less efficient at clearing debris and misfolded proteins, leading to the accumulation of toxic aggregates and chronic inflammation in the brain. Chronic microglial activation can cause neuroinflammation, damaging neurons and excessive synapse pruning, ultimately contributing to neurodegeneration. This thesis explores microglial phenotypes in various disease conditions and aging, aiming to understand how microglia acquire these disease-associated characteristics. In chapter 2, we demonstrated that treatment with minocycline to inhibit microgliosis at an early-stage prevented cognitive impairment in a mouse model of Alzheimer's disease. In chapter 3, we identified a set of genes that potentially reflects the initial response of microglia to amyloid. In chapter 4, we determined potential regulators of microglia acquiring a primed phenotype, which is associated with aging and neurodegenerative diseases. In chapter 5, we revealed that radiation induces persistent upregulation of microglia priming genes as well as exaggerated immune responses with a subsequent peripheral stimulus. Overall, the thesis delves into the microglial functions in different disease contexts and aging, shedding light on their contributions to neuroinflammation and neurodegeneration.