A number of transgenic mouse models have been developed to study the molecular and pathological alterations associated with Alzheimer’s disease (AD). The 3xTg mouse is widely used as a research tool and carries mutations in the amyloid precursor protein (Swedish APP K670N/M671L), presenilin 1 (PS1M146V) and tau (TauP301L) which results in the development of pathological features simlar to the plaques and tangles observed in human AD. The TASTPM mouse carries both the APP K670N/M671L and PS1M146V mutations but does not possess a tau transgene, so develops only plaque-like structures in the brain. This thesis aims to systematically characterise biochemical, electrophysiological and behavioural changes present in the 3xTg and TASTPM mouse models of AD. The widely studied amyloid cascade hypothesis proposes that the generation of Aß through abnormal APP processing is a key initiating process in AD, and so molecular or electrophysiological changes which are observed in both models could represent a common pathway of disease development. In addition, comparison between the two models could help to elucidate the role of the tau transgene in early phenotypic changes. The studies of hippocampal electrophysiology presented in this thesis show that the marked deficits in long-term potentiation (LTP) originally reported at the age of 6 months (Oddo et al., 2003) are not present in our colony of 3xTg mice. In support of this, although these mice do overexpress APP and tau the expected hyperphosphorylation of tau is not observed even at the advanced ages of 12-17 months. This suggests that some of the processes associated with the development of pathological features are occurring more slowly in our colony. In addition, studies using a T-maze paradigm in 6 month 3xTg mice suggest that major cognitive deficits are not present at this age. This suggests that drift of the phenotype has occured in the 3xTg mouse and has implications for further studies using this model. The 3xTg mouse does, however, present a deficit in basal synaptic transmission which is progressive with increasing age from 6-17 months. Similarly, hippocampal synaptic function is normal in TASTPM mice studied at 2 months, when no biochemical changes are present, but is markedly reduced at the age of 6 months when it proved difficult to make any electrophysiological recordings. The data in this thesis shows that treatment with 1mM kynurenic acid during the slicing process markedly improved baseline synaptic transmission to the level observed in control mice. This shows that kynurenic acid can improve the viability of the slices, and as the compound is a glutamate receptor antagonist, suggests that reduction of glutamate-induced excitotoxicity during the slicing process results in its neuroprotective effects. This data suggests that alterations common to the 3xTg and TASTPM models, and therefore due to the presence of the APP or PS1 transgenes, may result in an increased susceptibility of hippocampal neurons to cellular stressors such as excitotoxicity. To summarise, this thesis presents data which characterises in detail aspects of the electrophysiological, biochemical and behavioural phenotype of the 3xTg and TASTPM mouse models of AD, with the aim of observing early changes which may be associated with the mechanisms of AD development.
|Date of Award||2011|
|Supervisor||Calum Sutherland (Supervisor), Jeremy Lambert (Supervisor), Delia Belelli (Supervisor) & David Balfour (Supervisor)|