The present thesis explored a number of topics all linked by their involvement in Alzheimer’s disease (AD). Firstly, hippocampal slices prepared from a new transgenic knock-in mouse model of the disorder PLB1, harbouring human APP (with the Swedish and London mutations), Tau (with the P301L and R406W mutations) and PS1 (with the A246E mutation) genes were characterised electrophysiologically. Data obtained confirm AD-like alterations in PLB1 mice and suggest that these mice are a suitable model of AD and slice electrophysiology is a relevant experimental endpoint. Secondly, the effects of memantine on synaptic transmission and plasticity in the mouse hippocampus were investigated. Memantine was found to inhibit tetanus-induced LTP in the CA1 region at high concentrations (100 μM) while being devoid of such effects at lower (10 μM), therapeutically relevant doses. However, both concentrations acted to enhance baseline synaptic transmission via enhanced muscarinic signalling in a similar fashion to the muscarinic agonist carbachol, suggesting an additional facet to the drugs good clinical utility in AD patients. Thirdly, potential new treatments for AD were investigated in the form of a plant extract from <i>Cassia obtusifolia</i> (COE) and novel synthetic β-secretase (BACE) inhibitors LC25-116, LC25-120 and LC25-184. COE provided significant protection in models of excitotoxicity and mitochondrial dysfunction, both inherently linked to the pathogenesis of AD. The three novel BACE inhibitors significantly reduced Aβ production by an APP-expressing neuroblastoma cell line and reduced the resulting toxicity of its medium to hippocampal cultures. Finally, A1, a risk factor in AD, was investigated by assessing the toxicity of Al.cit.Q (K[A1(C<sub>7</sub>H<sub>11</sub>O<sub>6</sub>)<sub>3</sub>](OH]4H<sub>2</sub>O<sub>. </sub>The neuroprotective properties of quinic acid, the ligand attached to A1 in Al.cit.Q., were consequently tested. The results highlight the profound effect the ligand bound to A1 has on the metal’s toxicity and suggest that quinic acid could successfully be employed to combat metal toxicity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:510542 |
| Date | January 2009 |
| Creators | Drever, Benjamin David |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=26524 |
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