% 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”.

@ARTICLE{Riemenschneider:259006,
      author       = {Riemenschneider, Henrick and Simonetti, Francesca and
                      Sheth, Udit and Katona, Eszter and Roth, Stefan and Hutten,
                      Saskia and Farny, Daniel and Michaelsen, Meike and Nuscher,
                      Brigitte and Schmidt, Michael K and Flatley, Andrew and
                      Schepers, Aloys and Gruijs da Silva, Lara A and Zhou, Qihui
                      and Klopstock, Thomas and Liesz, Arthur and Arzberger,
                      Thomas and Herms, Jochen and Feederle, Regina and Gendron,
                      Tania F and Dormann, Dorothee and Edbauer, Dieter},
      title        = {{T}argeting the glycine-rich domain of {TDP}-43 with
                      antibodies prevents its aggregation in vitro and reduces
                      neurofilament levels in vivo.},
      journal      = {Acta Neuropathologica Communications},
      volume       = {11},
      number       = {1},
      issn         = {2051-5960},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DZNE-2023-00715},
      pages        = {112},
      year         = {2023},
      abstract     = {Cytoplasmic aggregation and concomitant nuclear clearance
                      of the RNA-binding protein TDP-43 are found in ~ $90\%$ of
                      cases of amyotrophic lateral sclerosis and ~ $45\%$ of
                      patients living with frontotemporal lobar degeneration, but
                      no disease-modifying therapy is available. Antibody therapy
                      targeting other aggregating proteins associated with
                      neurodegenerative disorders has shown beneficial effects in
                      animal models and clinical trials. The most effective
                      epitopes for safe antibody therapy targeting TDP-43 are
                      unknown. Here, we identified safe and effective epitopes in
                      TDP-43 for active and potential future passive
                      immunotherapy. We prescreened 15 peptide antigens covering
                      all regions of TDP-43 to identify the most immunogenic
                      epitopes and to raise novel monoclonal antibodies in
                      wild-type mice. Most peptides induced a considerable
                      antibody response and no antigen triggered obvious side
                      effects. Thus, we immunized mice with rapidly progressing
                      TDP-43 proteinopathy ('rNLS8' model) with the nine most
                      immunogenic peptides in five pools prior to TDP-43ΔNLS
                      transgene induction. Strikingly, combined administration of
                      two N-terminal peptides induced genetic background-specific
                      sudden lethality in several mice and was therefore
                      discontinued. Despite a strong antibody response, no TDP-43
                      peptide prevented the rapid body weight loss or reduced
                      phospho-TDP-43 levels as well as the profound astrogliosis
                      and microgliosis in rNLS8 mice. However, immunization with a
                      C-terminal peptide containing the disease-associated
                      phospho-serines 409/410 significantly lowered serum
                      neurofilament light chain levels, indicative of reduced
                      neuroaxonal damage. Transcriptomic profiling showed a
                      pronounced neuroinflammatory signature (IL-1β, TNF-α,
                      NfκB) in rNLS8 mice and suggested modest benefits of
                      immunization targeting the glycine-rich region. Several
                      novel monoclonal antibodies targeting the glycine-rich
                      domain potently reduced phase separation and aggregation of
                      TDP-43 in vitro and prevented cellular uptake of preformed
                      aggregates. Our unbiased screen suggests that targeting the
                      RRM2 domain and the C-terminal region of TDP-43 by active or
                      passive immunization may be beneficial in TDP-43
                      proteinopathies by inhibiting cardinal processes of disease
                      progression.},
      keywords     = {Animals / Mice / Antibodies, Monoclonal / Epitopes /
                      Immunization / Intermediate Filaments / NF-kappa B /
                      Antibodies, Monoclonal (NLM Chemicals) / Aggregation (Other)
                      / Amyotrophic lateral sclerosis (Other) / Frontotemporal
                      dementia (Other) / Immunotherapy (Other) / Neurodegeneration
                      (Other) / Phase separation (Other) / TDP-43 (Other) /
                      Epitopes (NLM Chemicals) / NF-kappa B (NLM Chemicals) /
                      TDP-43 protein, mouse (NLM Chemicals)},
      cin          = {AG Edbauer / AG Zhou / Neuropathology / Brainbank / AG
                      Herms / AG Feederle / Clinical Dementia Research München ;
                      AG Levin},
      ddc          = {610},
      cid          = {I:(DE-2719)1110004 / I:(DE-2719)5000080 /
                      I:(DE-2719)1140013 / I:(DE-2719)1110001 / I:(DE-2719)1140004
                      / I:(DE-2719)1111016},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 353 - Clinical and
                      Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC10334564},
      pubmed       = {pmid:37434215},
      doi          = {10.1186/s40478-023-01592-z},
      url          = {https://pub.dzne.de/record/259006},
}