Microglia and neuroinflammatory response during systemic infection

Systemic infection is an important risk factor for delirium, associated with neurodegeneration and subsequent cognitive impairment in older people. Microglial and neuroinflammatory response are known key players in this process. We hypothesize that impaired inhibitory control of microglia, during healthy aging and in a greater extent in neurodegenerative disease, contributes to an uncontrolled neuroinflammatory response during a systemic infection. In this thesis we summarized and reviewed available evidence from numerous animal studies on the effect of different systemic inflammatory stimuli on timing and intensity of microglial cell response (chapter 2) and introduced an animal model that closely simulates the clinical situation, where systemic challenge with live Escherichia (E.) coli induces microglial cell activation (chapter 3). We investigated the effect of healthy aging and observed more microglial activation and pro-inflammatory mediators in brain of aged mice after systemic infection, compared to young mice (chapter 4). We additionally examined two regulating receptors on microglial cells in knock-out mice, respectively triggering receptor expressed on myeloid cells 2 (TREM2) (chapter 5) and α7 nicotinic acetylcholine receptor (α7nAChR) (chapter 6). The role of both receptors in the neuroinflammatory response following systemic infection appears to be limited in knock-out mice. Taken together, this thesis provides a clinical relevant mouse model in which a microglia and neuroinflammatory response after systemic infection is found, which is evidently more pronounced in aged mice. However, we failed to find a responsible impaired inhibitory control on microglia using knock-out mice