Autosomal-dominant mutations in the amyloid precursor protein (APP) gene increase the production and aggregation of toxic amyloid-β (Aβ) peptides and cause early-onset Alzheimer’s disease (AD). Noradrenergic cell loss is well documented in AD and has been posited to play a role in cognitive symptoms as well as disease progression. We investigated memory and affect, tissue levels of catecholamines, brain-derived neurotrophic factor (BDNF) mRNA and bioenergetic homeostasis in TgCRND8 mice that express a double mutant (K670N/M671L + V717F) human APP695 transgene. We found that TgCRND8 mice develop object memory impairment and behavioural despair, as well as reductions in noradrenaline and BDNF expression in the hippocampus and cortex, before the appearance of Aβ plaques. Animals with more advanced Aβ pathology exhibit disruptions in energetic status, along with diminished complex I+III activity in the electron transport chain. To test whether the AD-like phenotypes of TgCRND8 mice might be due to altered noradrenergic tone, pre-plaque mice were treated with dexefaroxan, an antagonist of presynaptic inhibitory α2-adrenoceptors that are highly expressed on both noradrenergic and cholinergic terminals. Effects of dexefaroxan were compared to those of rivastigmine, a cholinesterase inhibitor. Both dexefaroxan and rivastigmine improved behavioural phenotypes and BDNF expression without affecting tissue Aβ load. Drug treatments also restored complex I+III mitochondrial activity and increased ATP levels. Reductions in noradrenergic tone appear to underlie Aβ-induced functional impairment in TgCRND8 mice, in addition to BDNF deficits and bioenergetic stress. These studies suggest that α2-adrenoceptor targeting may warrant consideration as a therapeutic strategy in AD.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/43559 |
| Date | 09 January 2014 |
| Creators | Francis, Beverly |
| Contributors | Mount, Howard |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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