216 Summary Neuroinflammation in neuroinflammatory and neurodegenerative diseases is only one of the many complex multicellular processes that occurs behind the ‘closed borders’ within the central nervous system (CNS). Two important innate immune cells in the CNS that contribute to damage as well as repair are microglia and astrocytes. Given their importance in many diseases there is an urgent clinical need to monitor glial cell activity during disease as well as assess the impact of medical intervention on innate immune responses during diseases. Positron emission tomography (PET) is one of the modalities to monitor neuroinflammation and pathological changes in neurodegenerative diseases and experimental animal in vivo. PET has the advantage of being able to interrogate various disease mechanisms by quantifying specific molecular targets to directly study the CNS. In this thesis we examined the cellular distribution and the regulation of the translocator protein (TSPO) in CNS resident cells in neurodegenerative diseases and their respective animal models. TSPO is generally through to be a marker of activated microglia and has been reported as such by many studies. Initial reports on animal models of neuroinflammatory diseases showed that TSPO is also expressed by other cell types than microglia but these findings have been largely ignored by PET studies, and the early human studies were qualitative rather than quantitative. Recently, it was shown in vitro that primary rodent microglia upregulate TSPO expression in a pro-inflammatory environment, while this is not the case in humans. Thus, findings of the triggers of TSPO, and the cellular expression of TSPO in the CNS in animal models may not translate to human disease. To investigate the cellular distribution and understand the triggers of TSPO we first performed in-depth studies of TSPO expression in MS to validate TSPO expression in glial cells and how the TSPO protein was regulated. Then we expanded our studies to other common neurodegenerative diseases such as AD and ALS and their respective animal models. In addition, we have utilised publicly available databases on TSPO regulation on multiple molecular levels. Another goal of the thesis was to investigate the role of microglia and astrocytes as innate immune cells of the CNS as they are becoming increasingly implicated in having diverse functions and heterogeneous states in many CNS diseases. While historically, microglia were considered as the phagocytes of the brain and astrocytes as responders to damage, the rise in advanced technologies such as single cell and single nucleus RNAseq, as well as detailed pathology studies made available by a plethora of antibodies and probes has shown that microglia and astrocytes have diverse and complex functions in the CNS. Together, these studies have allowed a more detailed understanding of the role of microglia and astrocytes as innate immune cells of the CNS. Chapter 2 describes the expression of the TSPO protein in MS compared to age-matched non-neurological controls. It features TSPO expression in glial cells in white and grey matter lesions in the brain and in the spinal cord. In this study we show that TSPO expression is not exclusive to activated microglia, as homeostatic microglia also express TSPO. Additionally we show that TSPO expression is not limited to microglia, but that astrocytes, and to a lower extent endothelial cells and oligodendroglia also are capable of TSPO expression in the CNS. We also show that TSPO expression is highly correlated with actual TSPO ligand binding that is used in the clinic for TSPO research and imaging neuroinflammation. The presence of TSPO in homeostatic microglia and astrocytes has implications for the interpretations of TSPO PET, and thus should be accounted for when interpreting this data.
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