Creating models of human disease is one important use of genetic modification in mammals. Where genetic mutations are known to produce a disorder in humans, those mutations can be reproduced in animals by using knock-out, knock-in or transgenic overexpression of the relevant genes. In the case of Alzheimer's disease, there are several mutations known to either produce (in an autosomal dominant fashion) or seriously increase the risk of developing the disease. By over-expressing one of these mutant proteins in mice, we have access to a model that not only allows us to study Alzheimer's disease in a way that is impossible in humans, but also may give us insight into the basic processes of learning and memory. Our investigations have focused on one particular line of transgenic mice that over-express a mutated form of the human amyloid-precursor protein (HuAPP). Although the specific mutation introduced in this case is rather rare, APP is implicated in most (if not all) cases of Alzheimer's disease. Thus, the overproduction of mutated HuAPP in these mice leads to many classic signs of Alzheimer's disease neuropathology, including elevated concentrations of beta-amyloid and its deposition into neuritic plaques. Our task in analysing this mice was to observe the development of behavioural and electrophysiological abnormalities, and to determine whether or not they are related to the presence of Alzheimer's-like neuropathology.
The transgenic approach means that we have some degree of confidence that the aetiology and developmental time-course are similar to those of the human disorder. The value of having the mouse model is that it permits us to use a range of approaches to get at the problem of how Alzheimer's disease begins, what physiological processes are affected (particularly in the early stages) and what we can do to reverse these processes. Thus, we can train the mice on a range of behavioural tasks (spatial reference memory, spatial working memory, recognition memory etc.), then do electrophysiological experiments on the same animals, either in vivo or in vitro, and finally, examine in detail any neurochemical or structural pathologies. This means that we can, in theory, determine whether working memory or reference memory deficits occur first, and whether one or the other of them are better correlated with (for example) LTP deficits in the dentate gyrus and soluble beta-amyloid, or with LTP deficits in CA1 and fibrillar amyloid deposits. In addition to reviewing some of the data that relate to this approach, it is worth our time to consider a strategy by which we can determine the appropriate sets of electrophysiological and behavioural tests to help us fully characterise the disorder at various stages of development. The conclusion I hope we can reach is that the examination of mouse models of Alzheimer's disease will give us insight into not only the disease itself.