Milton, R.H.;
(2010)
The effects of beta-amyloid peptide on microglial
function.
Doctoral thesis , UCL (University College London).
Abstract
The role of microglia in Alzheimer’s Disease (AD) pathogenesis is widely acknowledged, and the beta-amyloid (Aβ) peptide which accumulates in AD brain is known to activate a range of microglial functions. In the present thesis, the acute induction of some of these processes is examined using live cell imaging techniques. Aβ causes activation of microglial NADPH oxidase, a membrane-localised enzyme system which produces reactive oxygen species (ROS) thereby engendering oxidative stress. The transfer of electrons across the membrane by this enzyme system to produce ROS generates a potential difference, which will limit enzyme function unless it is dissipated by a compensatory movement of charge. I show that chloride intracellular channel 1 (CLIC1), a protein enriched in microglia and implicated in Aβ- induced microglial-mediated neurotoxicity, mediates a chloride conductance which sustains NADPH oxidase activity. Thus, blockade or knockdown of CLIC1 limits Aβ- induced ROS production. Using a variety of imaging methods, I show that the fascinating CLIC1 protein achieves its functions following an Aβ-induced redoxdependent direct insertion into the plasma membrane from the cytosol. Acute Aβ-induced microglial calcium signalling is also examined. Aβ is shown to elicit rapid and complex changes in microglial cytosolic calcium concentration, although these changes are less frequently observed in microglia than in astrocytes. The changes are not linked to ROS damage nor to voltage-gated calcium channel (VGCC) activity, but may be dependent on CD36 receptor function. The effects of Aβ treatment on subsequent calcium signalling elicited by the neuronal damage signalling molecule adenosine triphosphate (ATP) are investigated, and found to be complex. Aβ causes disruption of microglial calcium homeostasis and a reduction in the response to ATP, despite the calcium levels in the endoplasmic reticulum required for the response being increased. This work suggests that Aβ has diverse and consequential effects on microglial function relevant to AD pathophysiology.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | The effects of beta-amyloid peptide on microglial function |
| Language: | English |
| Additional information: | Authorisation for digitisation not received |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/19221 |
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