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| Home > Publications Database > W04-02: Tau toxicity and rescue in cell and animal models of tau pathology |
| Home > Publications Database > W04-02: Tau toxicity and rescue in cell and animal models of tau pathology |
| Abstract/Journal Article | DZNE-2020-00841 |
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2015
Abstract: Tau is a neuronal microtubule-associated protein. In AlzheimerDisease (AD), Tau is altered by hyperphosphorylation, mislocal-ization, aggregation etc. We study the physiological functions ofTau and its role in neurodegeneration in AD and other tauopathies. We are developing cell and animal models to observe the spreadingof Tau pathology, the interaction with A-beta, and the effects ofaggregation inhibitor compounds as a therapeutic approach. Thisincludes transgenic mice in which Tau is expressed either in a “ pro-aggregant” form, or in a non-aggregating form, which can becompared with Tau knockout mice or mice expressing wildtypeforms of Tau. Aberrant mislocalization and aggregation of Tau,combined with loss of synapses and microtubules are among thehallmarks of AD. Similar features are observed in mice expressingpro-aggregant Tau, but not with anti-aggregant Tau, illustrating thatthe propensity for beta-structure is at the root of aggregation andpathology. Microtubules play essential roles in the maintenance ofaxons and dendrites as tracks for intracellular transport by motorproteins. To elucidate the cascade of events leading to microtubulebreakdown we exposed mature wildtype and Tau knockout neuronsto A-beta oligomers and analyzed changes in the Tau/microtubulesystem. Microtubule breakdown occurs in dendrites invaded by Tauand is mediated by spastin, a microtubule-severing enzyme. Spastinin turn is recruited to microtubules modified by polyglutamylation,mediated by translocation of the enzyme Tubulin-Tyrosine-Ligase-Like-6. Photoconversion of Tau labeled with Dendra2 reveals thatmissorted Tau in dendrites is newly synthesized and not derivedfrom the axon. In absence of Tau (TauKO neurons), microtubulesand synapses are resistant to A-beta induced toxicity. The resultsprovide a rationale for microtubule stabilization as a therapeuticapproach. - Supported by DZNE (German Center for Neurodegen-erative Diseases), Max-Planck-Society, Tau Consortium.
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