Behavioural and cellular models of Alzheimer's disease : effects of aluminium, beta-amyloid and scopolamine in rats
Episodic memory deficits are early indicators of Alzheimer’s disease (AD) and have been attributed to hippocampal atrophy and cholinergic hypofunction. In over 90% of AD cases the cause is unknown. Aluminium (AI) is a putative environmental risk factor, which has been suggested to contribute to the development of the disease, possibly by interaction with intrinsic risk factors, such as beta-amyloid (bA). Great efforts are made to develop AD-like animal models, which mimic various aspects of the disease. This thesis had 3 main objectives: 1) to find a test suitable for detection and longitudinal testing of AD-like behavioural deficits in rats; 2) to assess the behavioural consequences of Al and/or bA administration, and 3) to assess the toxic properties of these compounds in vitro. 1) A spatial memory test employing the delayed-match-to-position paradigm was devised, to assess the retention of one-trial acquired spatial information over short (seconds) and long (hours) delays. The paradigm was sensitive to muscarinic antagonism by the classic amnestic drug scopolamine. 2) Various administration protocols of Al and bA were tested. Mostly subtle changes in behaviour were observed, but acute infusions of Al-citrate impaired performance and altered scopolamine sensitivity. 3) Primary rat hippocampal cultures treated with Al and/or bA confirmed toxicity of the compounds in AD-relevant concentrations. The chemical properties (e.g. pH and serum) of the solutions surrounding the cells had a major impact on cell survival. The effects were concentration- and time-dependent and generally affected neurones more than glial cells. While the in vitro data clearly confirm the toxic potential of Al and bA, it appears that the intact CNS is more resistant to such challenges. However, the subtle effects observed suggest that further refinement of administration and longer exposures may result in more pronounced effects.