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Mutated human genes associated with human neurodegenerative conditions were used to develop both <i>in vitro</i> and <i>in vivo</i> models to study cellular pathology and disease progression. The <i>in vitro</i> models employed adenoviral vectors for the gene delivery into primary rat hippocampal neurones. Introduction of both APP and Tau transgenes reduced neuronal viability, with the latter leading to accelerated toxicity and faster onset of cell death. Time-lapsing imaging analyses revealed apoptosis-like features for APP-positive neurones, while Tau-positive neuronal death appeared more necrotic. Interestingly, a direct correlation between cell death and protein content in the APP-transduced neurones was not confirmed. A comparison between viral gene delivery and electroporation with the same transgenic constructs confirmed the cellular toxicity of APP and Tau but also showed that with a lower amount of transgene expressing cells per culture dish Tau-induced toxicity was no longer as aggressive as with the viral model. Therefore, electroporation may allow single-cell investigations of functional parameters whereas the large amount of transgene-positive neurones in viral transductions allows faster quantification of cell death. These methods complement each other and thus offer <i>in vitro </i>models suitable for mechanistic studies and drug screening. Accordingly, initial testing of inhibitors of Tau aggregation and amyloid formation were found to ameliorate the transgene-induced damage as proof of principle for our novel <i>in vitro</i> models. Further testing revealed caffeine to be a very promising drug candidate in AD treatment, since it improved viability in both APP and Tau transduced neurones. The transgenic PLB1 mouse knock-in model harbours the same mutated APP and Tau genes as the viral models. A triple transgenic line (PLB1_Triple) has been generated with additional mutated presenilin 1 for increased APP processing and accelerated pathology. The mRNA expression of both APP and Tau transgenes was stable over the investigated time (6 and 12 months) with about 2 to 3-fold higher APP over Tau mRNA levels. This expression was specific to the forebrain and negligible in the cerebellum and thus targets a brain region that is vulnerable in AD. The model showed progressive accumulation of AD-linked histopathological features as well as memory- and activity-related symptoms. This low transgene expression in conjunction with a progressive phenotype is advantageous over other aggressive animals models for studying early disease-related pathology.

The first focus of this thesis was to determine whether motor learning and recognition memory was intact in Line 66+/+ mice, a mouse model which mimics neurodegenerative disease coupled with tau aggregation. Line 66+/+ display positive tau pathology in forebrain, hindbrain and spinal cord by 5 weeks of age. At 4 months of age Line 66+/+ mice were impaired in the motor learning task suggesting that tau pathology had decreased motor performance. Treatment with an anti tau aggregating drug reversed motor learning deficits in Line 66+/+ mice. At 5 months of age Line 66+/+ mice exhibited deficits in the social recognition. This result indicates that transgenic influences on Line 66+/+ mouse performance had extended to social memory function. The second focus of this thesis was investigating recognition memory of a novel triple transgenic model of AD, the PLB1 mouse model. Generation of the PLB1 mouse model came from the realisation that many of current mouse models for AD display major disadvantages in the fact that there is no control for the disturbance caused by the insertion of the transgene(s) with many of them lacking age-specificity, as well as brain-region and cell-type specificity. PLB1Double mice were generated using a knock-in procedure for integration of a single construct containing mutated APP and tau under the control of a forebrain- and age-specific CaMKII promoter. PLB1Double mice were crossed with a PSEN expressing mouse line generating the PLB1Triple line. APP and tau transgenes were flanked by floxed and flirted allowing direct comparison between animals containing one, two or three AD-relevant transgenes. PLB1Triple mice exhibit neuropathological changes by 6 months of age. PLB1mice displayed deficits in behavioural paradigms from 8 months of age suggesting that transgene inclusion had affected recognition of spatial, object and social information.