Kallo, Veronika; (2019) The effects of inflammation induced by LPS and alpha synuclein on iron homeostasis in glial and neuronal cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Inflammation is a key pathological feature of sporadic and hereditary neurodegenerative disorders mediated by resident activated glial cells; namely of microglia and astrocytes. These cells represent the innate immunity of the central nervous system by constantly inspecting the extracellular milieu and induce the inflammatory cascade in response to injury and infection in a very rapid manner. Hence, the activation of both cell types is necessary to maintain homeostasis required for neuronal function and host defense mechanisms. However, under chronic inflammatory conditions activated glial cells lose their protective nature and secrete excessive inflammatory cytokines and neurotoxic factors which have a deleterious burden on neuronal viability and may greatly contribute to the pathogenesis of neurodegenerative diseases. Iron accumulation is often jointly present with inflammation in brain areas where neuronal cell death is evident. Thus, the inflammatory cascade is strongly linked to iron homeostatic dysregulation. However, it is not clear how inflammation affects the iron metabolism of microglia, astrocytes and neurons. This thesis investigates the impact of the innate inflammatory response induced by (1); bacterial endotoxin; lipopolysaccharide and (2); purified recombinant human α-synuclein on iron metabolism of microglia, astroglia and the effect of these activated glial cells have on neuronal iron regulation in an in vitro co–culture system. Changes associated with iron metabolism and the inflammatory response was evaluated by measuring expression of genes, proteins and iron transport within activated glia and neurons exposed to pro-inflammatory glia. Results revealed that lipopolysaccharide and α-synuclein not only induce the inflammatory response in glia with the production of diverse pro-inflammatory species but also changes the gene expression profile of iron importer, storage and exporter proteins. Neuronal and glial co-culture studies further support the effect of inflammation on iron regulating proteins that show increased influx of iron in both neurons and glial cells. These results highlight that the inflammatory process can influence the iron content of brain cells and provide further grounds for investigating the role of iron in neurodegeneration.

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