Recent genome wide association studies in Alzheimer’s disease have highlighted the importance of the complement cascade in the pathogenesis of Alzheimer’s disease. However, the cellular and molecular roles of these complement proteins are not fully understood. Microglia express complement receptors and the activation of specific receptors may increase Aβ clearance and reduce/prevent neurodegeneration. The work presented in this thesis was aimed at investigating the contribution of Complement receptor 1 (CR1), the second most significant hit in GWAS studies, on microglia to neuronal damage. To explore the consequences of blocking CR1 to microglial-neuronal interactions, primary rat microglia were treated with a CR1 functional blocking antibody together with microglial activators for 24 h. It was found that microglia displaying an activated phenotype demonstrated an increase in CR1 expression. Activation of microglial CR1 was found to be detrimental to neurons and this correlated with an increase in microglial intracellular superoxide generation, nitric oxide (NO) production, tumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β) secretion. Amyloid-β 1-42 (Aβ1-42)-treated microglia displayed an increased ability to phagocytose dextran beads following antibody blockade of CR1 but a decreased capacity to phagocytose fluorescent-tagged Aβ1-42. CR1 immunoreactivity was investigated by immunohistochemistry in AD and control human post-mortem brain tissue. A higher level of CR1 immunoreactivity was found in areas of high Aβ plaque burden in AD brain tissue. A difference in CR1 expression on red blood cells between individuals was measured by flow cytometry. Together, these results indicate that microglial CR1 plays a role in the neuronal death observed in AD and investigating this further may provide a possible strategy to control neurotoxicity in the AD brain.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:602861 |
| Date | January 2014 |
| Creators | Crehan, H. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1425685/ |
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