Neurotrophin mediated signaling pathways common to the immune and nervous system

Abstract

Neuroinflammation subsumes inflammatory processes in the central nervous system(CNS). The insults causing for neuroinflammation are diverse: infections, traumatic brain injury, toxins, and autoimmunity are among these. In the periphery activated macrophages and dendritic cells represent the first line of defense - the innate immunity. In the central nervous system pro-inflammatory cytokines are released by microglia, the brain resident macrophages, and astrocytes. This induces neuroinflammation. For the progression of various neurodegenerative diseases, including, e.g., Alzheimer's Disease, neuroinflammation, and prolonged immune activity have been identified as a risk factor. In this thesis, I investigated which effects the chronic infection with the parasite Toxoplasma gondii (T. gondii) and thereby prolonged neuroinflammation take on the brains of different laboratory mouse strains. Additionally, I investigated whether these effects are in part mediated by the p75 neurotrophin receptor. Neurotrophins are secreted proteins that belong to a class of growth factors. They have shown to be capable of regulating neuronal survival, differentiation, growth, and maintenance among other. Intriguingly neurotrophins are also expressed and secreted by microglia and other cell populations of the immune systems and thereby represent a direct signaling connection between the CNS and the immune system. My data shows that the C57BL/6 (B6) mouse strain is more susceptible to the parasite than BALB/c mice. Additionally to a significant weight loss upon infection B6 mice also show more drastic changes in neuronal morphology than BALB/c mice. Both strains react strongly microglial activation to T. gondii infection. Interestingly microglial morphology upon infection is strain specific and display different phenotypes. The second part of the data shows that B6 mice lacking the p75 neurotrophin receptor (knock out) show a milder reaction to the T. gondii infection on their neuronal architecture compared to the wild type.