With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits and an ageing population, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. Ongoing research suggests that soluble amyloid-β oligomers (Aβo) and inflammatory processes are among the early factors that contribute to the pathogenesis and progression of AD, by initially triggering synaptic deficits and subsequent cognitive impairment. The aim was to investigate cognitive and synaptic function, as well as neuroinflammatory markers, following an acute intracerebroventricular (ICV) injection of stabilised low-n Aβo in the rat.This thesis first investigates the different existing rat models of Aβ-peptide administration to better understand the mechanisms involved, neuropathological changes observed and cognitive deficits assessed. From this review, I determined the cognitive and neuropathological markers that would be investigated in the current model.After presenting all the methods used, the following results chapter studied the reproducibility and duration of the cognitive deficits, the effect of different doses of oligomers and sex differences. An early (4 days after surgery) and lasting (up to 70 days after surgery) memory deficit in the novel object recognition (NOR) task has been found. This deficit was triggered by doses of acutely administrated Aβo ranging from 0.5 to 5nmol, and equally affected female and male rats. Investigated neuropathological markers showed a synaptic deficit, raised neuroinflammatory cytokines levels and decreased density of parvalbumin-positive cells in the frontal cortex, but not the hippocampus. The NOR deficit could be rescued by treatment with the phosphodiesterase-4 inhibitor rolipram, an effect that stopped after cessation of the treatment. Treatment with the non-steroidal anti-inflammatory drug mefenamic acid prevented the NOR deficit and had an added protective effect up to 21 days after cessation of the treatment.Taken together, these results suggest that acute ICV administration of Aβo may be a useful model to study the early mechanisms involved in AD and may provide researchers with a platform for testing novel therapeutic approaches targeting the mechanisms that contribute to AD, and particularly the early neuroinflammatory phenomenon.
|Date of Award
|31 Dec 2016
- The University of Manchester
|Michael Harte (Supervisor) & Joanna Neill (Supervisor)