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@ARTICLE{Trambauer:276805,
      author       = {Trambauer, Johannes and Sarmiento, Rosa Maria Rodriguez and
                      Garringer, Holly J and Salbaum, Katja and Pedro, Liliana
                      Domingues and Crusius, Dennis and Vidal, Ruben and Ghetti,
                      Bernardino and Paquet, Dominik and Baumann, Karlheinz and
                      Lindemann, Lothar and Steiner, Harald},
      title        = {γ-{S}ecretase modulator resistance of an aggressive
                      {A}lzheimer-causing presenilin mutant can be overcome in the
                      heterozygous patient state by a set of advanced compounds.},
      journal      = {Alzheimer's research $\&$ therapy},
      volume       = {17},
      number       = {1},
      issn         = {1758-9193},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2025-00330},
      pages        = {49},
      year         = {2025},
      abstract     = {Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in
                      length (Aβ42/43) trigger Alzheimer´s disease (AD) and are
                      produced in abnormal amounts by mutants of the γ-secretase
                      subunit presenilin-1 (PS1), which represent the primary
                      cause of familial AD (FAD). Lowering these peptides by
                      γ-secretase modulators (GSMs) is increasingly considered a
                      safe strategy to treat AD since these compounds do not
                      affect the overall cleavage of γ-secretase substrates. GSMs
                      were shown to modulate not only wild-type (WT) γ-secretase
                      but also FAD mutants, expanding their potential use also to
                      the familial form of the disease. Unlike most other FAD
                      mutants, the very aggressive PS1 L166P mutant is largely
                      resistant to GSMs. However, these data were mostly obtained
                      from overexpression models, which mimic more the less
                      relevant homozygous state rather than the heterozygous
                      patient situation.Mouse embryonic fibroblast and induced
                      pluripotent stem cell-derived neuronal PS1 L166P knock-in
                      (KI) cell models were treated with various GSMs and Aβ
                      responses were assessed by immunoassays and/or gel-based
                      analysis.We identified GSMs that lower Aβ42 and/or Aβ43
                      when PS1 L166P is heterozygous, as it is the case in
                      affected patients, and could reduce the amount of pathogenic
                      Aβ species towards WT levels. RO7019009 was the most potent
                      of these compounds, reducing both pathogenic species and
                      concomitantly increasing the short Aβ37 and Aβ38, of which
                      the latter has been associated with delayed AD progression.
                      Another effective compound, the structurally novel
                      indole-type GSM RO5254601 specifically acts on the Aβ42
                      product line leading to a selective increase of the
                      beneficial Aβ38. Interestingly, we further found that this
                      class of GSMs can bind not only one, but both presenilin
                      fragments suggesting that it targets γ-secretase at an
                      unusual binding site.Our data show that even highly
                      refractory presenilin FAD mutants are in principle tractable
                      with GSMs extending the possibilities for potential clinical
                      studies in FAD with suitable GSM molecules.},
      keywords     = {Humans / Animals / Amyloid Precursor Protein Secretases:
                      metabolism / Amyloid Precursor Protein Secretases: genetics
                      / Alzheimer Disease: genetics / Alzheimer Disease: drug
                      therapy / Alzheimer Disease: metabolism / Presenilin-1:
                      genetics / Mutation / Amyloid beta-Peptides: metabolism /
                      Amyloid beta-Peptides: genetics / Mice / Heterozygote /
                      Peptide Fragments: metabolism / Peptide Fragments: genetics
                      / Induced Pluripotent Stem Cells: drug effects / Induced
                      Pluripotent Stem Cells: metabolism / Alzheimer’s disease
                      (Other) / Aβ (Other) / Familial Alzheimer’s disease
                      (Other) / Presenilin (Other) / γ-Secretase modulator
                      (Other) / Amyloid Precursor Protein Secretases (NLM
                      Chemicals) / Presenilin-1 (NLM Chemicals) / Amyloid
                      beta-Peptides (NLM Chemicals) / Peptide Fragments (NLM
                      Chemicals) / PSEN1 protein, human (NLM Chemicals)},
      cin          = {AG Steiner / AG Simons},
      ddc          = {610},
      cid          = {I:(DE-2719)1110000-1 / I:(DE-2719)1110008},
      pnm          = {352 - Disease Mechanisms (POF4-352) / 351 - Brain Function
                      (POF4-351)},
      pid          = {G:(DE-HGF)POF4-352 / G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39972463},
      doi          = {10.1186/s13195-025-01680-3},
      url          = {https://pub.dzne.de/record/276805},
}