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Title: Differential microglial activation in neurodegenerative diseases
Author: Pey, Peixuan
ISNI:       0000 0005 0732 4195
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Inflammation is thought to be a pathological feature that drives the neuronal degeneration in Alzheimer (AD) and Parkinson's diseases (PD). This is normally associated with classically activated microglia, which release pro-inflammatory cytokines. Recently, the heterogeneous nature of microglial activation states has been acknowledged and the focus has been shifting to the alternative activation state, an immunosuppressive state that promotes tissue maintenance and repair. This project examined microglia phenotypes in AD and PD, focusing on alternative activation and phagocytosis. Traumatic brain injury (TBI) cases were also studied to provide a comparison between an acute inflammatory reaction and chronic inflammation observed in AD and PD. An initial test using a battery of antibodies against microglia e.g. MHCII, Iba1, CD68, MRC1 was used to identify interesting targets for characterization in AD and PD. CD163 and CD14, both of which are thought to be exclusive to perivascular macrophages, were detected in parenchymal microglia in AD and PD, with a much more florid reaction observed in AD. Many of these microglia were associated with extracellular pathology i.e. Abeta plaques and extracellular Lewy Bodies. Experimental evidence from AD, PD and TBI cases suggest that these microglia were of local and systemic origin. A number of clinicopathological correlations were found in PD cases. Upregulation of CD14+ microglia in the substantia nigra was significantly correlated with absence of gait and balance problems as an onset symptom. Upregulation of CD163+ microglia in the cingulate cortex, entorhinal cortex, and locus coeruleus was significantly correlated with a lack of anxiety. In TBI cases, positive association was found between the upregulation of CD163+ microglia and survival time. My study demonstrates differential microglial activation in AD and PD, emphasizes the heterogeneity of microglia phenotype, and provides an insight into the influence of systemic inflammation on microglial activation.
Supervisor: Gentleman, Stephen Sponsor: Imperial College London ; National Institutes of Health (U.S.)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral