Biochemistry and Pharmacology - Theses
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ItemMicroglia and type-I interferons: emerging actors in Alzheimer’s disease( 2021)Alzheimer’s disease (AD) remains the most common cause of dementia worldwide. Post-mortem brains of AD individuals reveal classical pathological hallmarks of amyloid plaques and hyper-phosphorylated tau throughout the regions of the cortex and hippocampus. However, there have been few successes in therapeutics targeting these pathologies to treat AD, therefore suggesting new approaches are required. Recent evidence suggests that neuroinflammation, once thought inconsequential, contributes to AD progression. AD brains display enhanced gliosis surrounding plaques and elevated levels of pro-inflammatory cytokines. The characterisation of central nervous system (CNS) cell types and specific mediators of this neuroinflammatory response is critical in the identification of much- needed therapeutic targets to limit the damage in the AD brain. Our laboratory has previously identified that the type-I interferons (IFNs) are critical mediators of neuroinflammation contributing to the cognitive decline in a murine AD model. This thesis aimed to further characterise the specific effects of the type-I IFNs on microglia, a resident CNS immune cell. This thesis posits that type-I IFN mediated neuroinflammation modulates microglial phenotype contributing to the progression of AD pathology. This thesis aimed to investigate how type-I IFNs alter microglial phenotype and function in response to AB1-42, the key component of amyloid plaques, using both in vitro and in vivo murine models. From this study it was confirmed that microglia mount both pro-inflammatory and type-I IFN responses to AB1-42, of which both are ablated in Ifnar1-/-microglia, which lack the type-I IFN receptor. This finding was then extended to investigate if this phenotypic change manifested in altered functional changes in the ability of microglia to phagocytose or take up and internalise particles. Both IFNa and IFNb decreased the ability of microglia in vitro to phagocytose both bio-particles and fluorescently tagged AB1-42. This was investigated further in vivo, in mice that had received intra-hippocampal injections of AB1-42. No changes were observed in measures of AB uptake at 1-, 2- or 4-week post injection between wildtype and Ifnar1-/- mice. Mice with reduced type-I IFN signalling did, however, display decreased expression levels of Il6 and an altered astrocytic response within the hippocampus, suggestive of a lessened inflammatory response to AB1-42. Type-I IFNs are known to be elevated in aging, the largest risk factor for AD. This thesis took an in silico approach to compare type-I IFN expression between “normal” ageing and AD to gain a greater understanding of its role in driving the pathological changes in the AD brain. Using publicly available RNASeq datasets, this confirmed significant overlaps between type-I IFN related genes upregulated throughout both ageing and AD. This was most evident when examining a dataset containing purified cell types where there is a distinct lack of differences between controls and AD individuals. One of these genes, ISG20 was validated in a post-mortem human AD cohort and found to be significantly upregulated by QPCR and western blot analyses, supporting future investigations into its role in the disease pathogenesis. This thesis has built on previous findings from both our lab and others on the diverse roles of the type-I IFNs within the CNS and in AD. Specifically, it has identified and characterised a novel role for the type-I IFNs in modulating phagocytosis, a cellular process important in not only AD but several other neurodegenerative disorders. This thesis took a bioinformatic approach to identify a novel gene involved in AD, highlighting the increasing power of these tools and data when combined with traditional wet lab approaches to identify potential new therapeutic targets. Ultimately, this thesis forms a solid foundation to build upon and aid in the development of novel and much needed therapeutic approaches to slow AD progression.