Alzheimer's disease is a neurodegenerative disease that has many pathological features including; plaques and tangle formation and neuronal and synaptic loss. Deposits of ß-amyloid protein are found in the center of plaques. Its precursor is known as amyloid precursor protein (APP) and is believed to play a role in such diverse activities as cell adhesion and memory formation. This thesis has investigated the effect of both the deletion and overexpression of APP on the morphology of the hippocampus, in particular the dentate gyrus, in transgenic mice using unbiased stereological methods, at both the light and electron microscope level (1) Increases in synapse density and contrastingly decreases in apposition mean area were seen in APP knockout mice at 10/12 months when compared with age matched wild-type (wt) mice controls. A longitudinal study was carried out in APP overexpressing mice (Tas 10 mice) at ages 6, 12, 18 and 24 months. (2) Features of degeneration could be seen in the Tas 10 mice as young as six months but deposits of Aß and plaques were not seen by electron microscopy until the 18 and 24 month time points. (3) Decreased numbers of neurons were seen in Tas 10 in all age groups when compared with wt mice. (4) An increase in the number of synapses per neuron and a decrease in apposition zone mean size was seen in the middle molecular layer at 12 months (compared with wt mice) which then fell at 18 months and was then seen to decrease further by 24 months. Results from experiments on knockout mice endorse roles for APP in development and synaptogenesis although they support the idea that an overlap of function between APP and its family of proteins occurs. The results from the series of experiments on the Tas 10 mice strongly suggest the importance of APP in the development of certain features of AD and highlight this as a good model to study diseases associated with amyloidosis.
