218 Chapter 6 gives a short insight into the expansive effects of axonal loss on neurodegeneration and clinical disability in MS. We investigated the amount of axonal loss in the spinal cord of MS patients and correlated this with the presence of synapse proteins and the loss of local neurons. We found that the amount of synaptic pathology is extensive in MS spinal cord, the number of synaptic boutons, responsible for neuronal communication, were almost reduced to zero in lesional grey matter when compared to healthy spinal cord tissue. Additionally people with MS had a significant loss of spinal cord neurons. However, the loss of synaptic boutons did not correlate with the loss of neurons in the grey matter in the spinal cord. We concluded that axonal loss and neuronal loss in MS is extensive and higher than previously reported in the literature. Chapter 7 explores the immunomodulatory roles of astrocytes and oligodendrocytes, glial cells that are not commonly seen as having immune functions. Astrocytes have long been seen as bystanders during immune-related events in the CNS. Oligodendrocytes have long been seen as the victims of neuroinflammation. An increasing body of literature is pointing towards more complex roles for glial cells during immune activation. We found that astrocytes and oligodendrocytes have important cell-to-cell communication during inflammation. Astrocyte and oligodendrocyte play active roles as innate immune cells by secreting chemokines, and thus can influence other glial cells as well as each other. Chapter 8 is highlighting an important topic that is becoming increasingly important with the development of new technologies. Historically microglia are seen as the resident macrophages of the CNS, new techniques have highlighted diverse roles and their main functions in the CNS are to protect it from potential harm as well as regulate homeostasis. We show that microglia are diverse and have multifaceted roles in the white matter of the brain. Microglia have regionally defined functions related to development, homeostasis, ageing and in response to injury, reflecting the local need of the CNS parenchyma. This heterogeneity takes form in differences in density, morphology, and the transcriptome. We raise important questions that the field needs to take into account in future research while investigating microglia heterogeneity. Such as, ‘How similar are mouse (or other animals) and human white matter microglia?’ and ‘How stable are white matter microglial states?’. By raising awareness for these important questions we hope to stimulate the field into investigating the diverse microglia functions to eventually develop microglial based therapies. Overall, this thesis shows that TSPO is differently regulated in humans compared to mice and that all glial cells act as innate immune cells. The main conclusions per chapter are: • Microglia but also astrocytes express TSPO in MS lesions, TSPO PET reports on cell density rather than activation state (Chapter 2) • TSPO is not upregulated in activatedmicroglia inMS lesions compared to homeostatic microglia in the NAWM and in control white matter (Chapter 3) • Regulation of TSPO is phylogenetically diverse between humans and rodents, resulting in differential regulation of the TSPO gene in humans. TSPO is not increased in activated microglia and astrocytes in human CNS diseases (Chapter 4) • TSPO binding, cellular origin, and functional significance is dependent on many factors such as the pathology or the experimental animal model (Chapter 5) • Microglial activation in the MS spinal cord is associated with synaptic loss, resulting in progressive clinical disability (Chapter 6)
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