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Title: Animal models for novel drug treatments of tauopathies
Author: Deiana, Serena
ISNI:       0000 0001 3421 4881
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2008
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A transgenic animal model in which tau protein aggregation is expected to produce behavioural symptoms similar to those observed in certain tauopathies in humans has been examined in this thesis. The transgenic mouse lines, when tested in a heterozygous genetic background, showed no cognitive deficit although non-associative learning was impaired. Fine motor learning and motor coordination, however, were severely compromised suggesting disruption of cerebellar and/or basal ganglia function. This model can be used to test tau aggregation inhibitors, that may be effective in preventing, or even reversing the behavioural symptoms caused by tau-aggregation. Since the cholinergic deficit is a feature of Alzheimer’s disease, the effect of the inhibitors described above was tested on the cholinergic system. This was examined using a pharmacological model in which cholinergic deficit was induced by treatment of mice with scopolamine, a competitive antagonist at M1 muscarinic acetylcholine receptors. For the four tau aggregation inhibitors tested in the present work, there were differing efficacies in reversing the scopolamine-induced cognitive deficit. TRx0014 (methylene blue) was the most effective and more so than rivastigmine, a marketed cholinesterase inhibitor. Co-administration of TRx0014 and rivastigmine at sub-effective doses showed a synergistic effect on the reversal of cholinergic deficits. In conclusion, the present work provided a novel transgenic animal model that closely mimics certain behavioural traits typical of some tauopathies. These animals thus provide a valuable model to test novel tau aggregation inhibitors with potentially disease-modifying consequences. The study also demonstrates that such inhibitors, in addition, are able to reverse the symptoms due to cholinergic disruption in normal mice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available