| Shrnutí: | <p>Microtubule-associated protein tau plays an important role in many neurodegenerative diseases. By using and creating various novel mouse models, the role of tau and its relationship with other amyloidogenic proteins was investigated.</p> <p>Behavioural and molecular characterization of novel mouse models expressing all six isoforms of human wild-type (H1) or N296H mutant (N51) tau protein was carried out to study the age-related emergence of phenotypes commonly associated with tauopathies. Mutant animals displayed no degenerative cognitive or motor phenotype. However, a possible mood phenotype was observed even at a young age. No formation of intracellular tau inclusions was observed. Using acute slice cultures, I further investigated phosphorylation of N296H mutant tau. Relative tau hypophosphorylation was observed in a N296H mutant compared to the wild-type tau expressing animals. In the hippocampus, exposure to Abeta led to an increase in tau phosphorylation at S202/T205 in H1, but not N51 mice. Electrophysiological studies by M. Vargas-Caballero showed that H1, but not N51 animals are susceptible to Abeta-induced LTP impairment. Taken together, these results suggest that tau phosphorylation could mediate the effects of Abeta on LTP. N51 mice also showed a trend towards increased fyn expression. Fyn relocalization into the soma was not detected either in N51 or tau knockout animals. </p> <p>The functional relationship between tau and α-synuclein was investigated in several novel models. Neither acute exposure of acute slices to α-synuclein oligomers nor α-synuclein overexpression induced tau hyperphosphorylation. A novel mouse model lacking both tau and α-synuclein was generated, but revealed no remarkable behavioural changes. Finally, a new mouse model was created overexpressing human wild-type α-synuclein on a tau knockout background to investigate whether tau is required for α-synuclein-induced dopamine release deficits previously observed in α-synuclein overexpressors. </p>
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