% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@PHDTHESIS{Hebestreit:275903,
      author       = {Hebestreit, Alina},
      title        = {{A} {C}ell {P}anel to {C}haracterise {T}au {A}ggregation},
      school       = {Rheinische Friedrich-Wilhelms-Universität Bonn},
      type         = {Dissertation},
      reportid     = {DZNE-2025-00136},
      pages        = {125 p.},
      year         = {2025},
      note         = {Dissertation, Rheinische Friedrich-Wilhelms-Universität
                      Bonn, 2024},
      abstract     = {Tauopathies are neurodegenerative diseases characterised by
                      the pathological folding of Tau into highly ordered,
                      !3-sheet rich fibrils (so-called amyloid), which
                      progressively spreadthrough the central nervous system in a
                      prion-like manner. Despite extensive research, interand
                      intracellular prion-like Tau aggregate formation and
                      transmission mechanisms remainunresolved. Tauopathies can be
                      classified based on the aggregating Tau isoforms, which
                      differ in the number of amino-terminal inserts (1 N, 2N) and
                      the number of repeats (3R or 4R).Cryogenic electron
                      microscopy (cryoEM) revealed distinct Tau amyloid core
                      structures associated with different Tauopathies. The
                      clinical presentation and progression of these diseases are
                      highly variable, potentially related to the accumulation of
                      disease-specific Tau aggregates with amyloid cores that
                      comprise shorter or longer stretches of the repeat
                      region.However, the impact of these distinct amyloid folds
                      on the prion-like spreading of Tau aggregates remains to be
                      fully understood. This project had two aims. First, we used
                      a semiautomatedhigh-throughput screen to identify Tau
                      aggregation inhibitors. A previously established HEK cell
                      line expressing the P301 LJV337M Tau 4R repeat domain was
                      used for the screen. Two hits were identified in a library
                      of 144 compounds that effectively inhibited Tau aggregation.
                      Second, a cell panel expressing different Tau fragments
                      based on the cryoEM Tau amyloid cores was established. The
                      commonly used Tau repeat domain fragments might not
                      represent the most suitable model to study Tau aggregation
                      as the length of the Tau variants might affect its fibril
                      conformation. The exact regions that form the core of the
                      amyloid fibril might allow only selective intramolecular
                      interactions, potentially enabling disease-specific seeding.
                      Therefore, we established cell lines expressing the short
                      cryoEM Tau core fragments associated with different
                      Tauopathies (AD, CBD, PSP and PiD). Our data showed that
                      highly expressed cryoEM Tau core fragments spontaneously
                      aggregate. Cells with weak stable expression and no
                      spontaneous aggregation were generated to investigate
                      fibril-induced seeding. We demonstrated that the length and
                      number of repeats of our Tau fragments influence the
                      efficiency by which they are misfolded by exogenous Tau 3R
                      or 4R fibrils. Tau fragments were seeded best by
                      patient-derived Tau fibrils with an amyloid core of
                      identical length and repeat number. The length of the
                      expressed cryoEM Tau core fragments likely allows only the
                      assembly of specific core conformations due to possibly
                      fewer and more selective intramolecular interactions. In
                      summary, our cell panel can discriminate between 3R, 4R and
                      mixed 3R/4R Tauopathies. The inter- and intracellular
                      mechanisms involved in Tau aggregation and propagation can
                      be investigated using our cell panel assay. Our data can
                      help to develop new therapeutic strategies to inhibit or
                      reduce the aggregation of Tau by compounds.},
      cin          = {AG Vorberg},
      cid          = {I:(DE-2719)1013004},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)11},
      urn          = {urn:nbn:de:hbz:5-80578},
      url          = {https://pub.dzne.de/record/275903},
}