Özcelik, Sefika. Mechanisms of tau fragmentation, aggregation and degradation in transgenic mouse models. 2013, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_10701
In the first part of our studies, we analyzed a novel inducible transgenic mouse model (TAU62 mice), expressing a truncated form of human wild-type tau (tau151-421, noted tau). TAU62 mice displayed axonal dysfunction and slowly progressive motor phenotype. Importantly, the neurotoxicity of tau was strongly enhanced when full-length P301S tau was co-expressed. In particular, P301SxTAU62 (abbreviated P62) double transgenic mice showed rapidly progressive, severe motor impairment, which was reversed by stopping the tau expression. Consistently, neuronal dysfunction and tau hyperphosphorylation were reversed in P62 mice when expression of tau was switched-off. These results demonstrate that tau exacerbates the toxicity of full-length tau and thereby induces severe but reversible neuronal dysfunction associated with structural changes. In parallel, we showed that induction of autophagy, using the mTORC1 inhibitor rapamycin, is sufficient to improve tau clearance in a transgenic mouse model of tauopathy (P301S mice). Rapamycin significantly delayed the progression of tau pathology in P301S mice, which was associated with a reduction in the accumulation of insoluble tau.
Together, these data provide novel insights into the pathogenesis of tauopathies. They pave new ways for novel therapeutic strategies, which can prevent the fragmentation of tau and/or promote the process of autophagy.
|Committee Members:||Winkler, David and Staufenbiel, Matthias|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Pharmacology/Neurobiology (Barde)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||97 p.|
|Last Modified:||30 Jun 2016 10:55|
|Deposited On:||02 May 2014 10:12|
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