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

• Applicant: Professor Dr. Roland Brandt
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 414054805

The spatially and temporally tightly controlled polymerization of microtubules and the activity and regulation of microtubule-interacting factors such as the tau proteins play a crucial role in fundamental physiological and pathological processes in nerve cells. In particular, so-called tauopathies such as Alzheimer's disease are characterized by pathological aggregation of tau and a disorder of the neuronal cell skeleton. In the first phase of the project application, we developed various tools to quantitatively analyze the structure and function of microtubules in nerve cells and the influence of the development of an age-dependent tau modification. In particular, our work has shown that a single tau cleavage can induce a toxic gain in function by putting a brake on axonal transport, resulting in dendritic atrophy. Furthermore, we have established a single-molecule technique to obtain high-resolution images of microtubule organization in neuronal processes, which allows us to quantitatively evaluate changes in axonal microtubule organization. Third, we have developed a cellular assay system that allows us to answer long-standing questions related to the molecular and functional interaction of the aging of the cytoskeleton and tau aggregation. In the renewal application, we intend to apply these techniques to investigate the role of other critical pathological tau features such as hyperphosphorylation and tau aggregation in the development of tauopathies and to determine the potential of microtubule modulators. In particular, we want to answer two key questions: (1) How does disease-associated tau hyperphosphorylation affect microtubule structure and function and what is the main driver of tau-dependent neuronal degeneration? Our aim is to test the hypothesis that disease-associated tau modifications do not directly disturb microtubule organization, but rather induce alteration of other microtubule-regulating proteins, which then leads to the disruption of microtubule arrangement observed in Alzheimer’s disease and other tauopathies. (2) How do pathogenic tau mutations and tau aggregation affect the structure and function of axonal microtubules and can this be prevented by microtubule-modulating agents? Here we aim to follow the hypothesis that pathogenic tau mutations and tau aggregation disrupt the organization and function of axonal microtubules, leading to neuronal degeneration. In turn, we hypothesize that appropriate microtubule modulators that restore physiological organization of axonal microtubules have the potential to slow or even prevent neurodegeneration during tauopathies.

• DFG Programme: Research Grants