Analysis of the Involvement of the Microtubule Associated Protein Tau in the Regulation and Dysregulation of Neuronal Microtubule Dynamics by Quantitative „Live Cell Imaging“

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Microtubules (MT) are of particular importance in nerve cells, where they support the formation and stabilization of axons and dendrites, and ensure effective intracellular transport. Thus, it is not surprising that abnormalities of the MT skeleton, and the formation of aggregates of cytoskeletal proteins such as the microtubule-associated protein (MAP) tau are typical neuropathological features, which occur in several neurodegenerative diseases. Quantitative "live cell Imaging" has opened the possibility to scrutinize these processes in living neuronal cells. Using "single molecule tracking" (SMT) experiments we showed previously that tau exhibits a remarkably short dwell time (~40 ms) on a single MT-binding site in axon-like processes before it "hops" to the next one – a feature, which we termed "kiss and hop". However, important aspects for understanding the "kiss and hop" mechanism and its physiological and pathological relevance are still open. In a first project part, we plan to investigate the factors influencing the "kiss and hop" interaction of tau in nerve cells and its potential physiological and pathological consequences. In a second project part, we plan to identify critical disease-associated tau modifications, which lead to pathological changes in MT-based activities. We will also perform a cell biological characterization of potential drugs with the capacity to modulate disease-associated changes of tau and MT dynamics as a prerequisite to develop specific mechanism-based therapeutic options.