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@ARTICLE{Saleem:285729,
      author       = {Saleem, Tayyaba and Möbius, Wiebke and Schmitz, Matthias
                      and da Silva Correia, Angela and Thomas, Carolina and
                      Canaslan, Sezgi and Hermann, Peter and Goebel, Stefan and
                      Zafar, Saima and Root, Elisabeth and Stadelmann, Christine
                      and Andreoletti, Olivier and Hoppert, Michael and Fleming
                      Outeiro, Tiago and Ferrer, Isidre and Younas, Neelam and
                      Zerr, Inga},
      title        = {{A} distinct tau oligomer strain defines the molecular and
                      proteomic landscape of rapidly progressive {A}lzheimer's
                      disease.},
      journal      = {Acta neuropathologica},
      volume       = {151},
      number       = {1},
      issn         = {0001-6322},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DZNE-2026-00286},
      pages        = {27},
      year         = {2026},
      abstract     = {Rapidly progressive Alzheimer's disease (rpAD) is a rare
                      subtype with rapid decline, but its molecular underpinnings
                      remain poorly defined. Here, brain-derived tau oligomers
                      (TauO) were systematically compared across nondemented
                      controls, slowly progressive AD (spAD), and rpAD to test
                      whether subtype-specific TauO signatures align with clinical
                      aggressiveness. TauO were immunoprecipitated from frontal
                      cortex using T22 antibody and characterized by Western
                      blotting, transmission electron microscopy, label-free
                      quantitative proteomics, and SH-SY5Y toxicity assays,
                      complemented by longitudinal analysis of tau phosphorylation
                      in inoculated 3xTg AD mice. T22-positive
                      high-molecular-weight TauO were successfully enriched from
                      all groups, where rpAD TauO exhibited compact, densely
                      packed oligomers under TEM and the highest phosphorylation
                      at pS396 and pS422, exceeding both spAD and controls (p ≤
                      0.0327). In 3xTg mice, pS396 showed an early increase
                      followed by a late decline, consistent with dynamic shifts
                      in tau solubility during disease evolution. Brain-derived
                      TauO from spAD and rpAD, but not recombinant tau monomers or
                      control-derived TauO, significantly reduced SH-SY5Y cell
                      viability. Proteomic profiling identified 2388
                      TauO-associated proteins, including a shared 556-protein
                      core and a striking expansion of rpAD-unique interactors (n
                      = 1101). In controls and spAD, the core TauO interactome was
                      enriched for translation, proteostasis, mitochondrial
                      respiration, and vesicle-trafficking pathways, whereas these
                      modules were absent in rpAD. Instead, rpAD TauO showed
                      selective enrichment of aldehyde detoxification, amino-acid
                      and carbon metabolism, and actin-regulatory modules,
                      alongside increased association of SERPINA1, ALDH9A1,
                      MAPRE3, DPYSL2, DPYSL3, and NFASC and reduced coupling to
                      mitochondrial (MRPL17) and complement (C9) components. These
                      convergent structural, post-translational, toxic, and
                      interactome changes indicate that rpAD is defined by a
                      biochemically distinct TauO species embedded in a metabolic
                      and cytoskeleton-focused network, providing a mechanistic
                      framework for its aggressive clinical course and a basis for
                      subtype-specific biomarker and therapeutic strategies.},
      keywords     = {Alzheimer Disease: metabolism / Alzheimer Disease:
                      pathology / Alzheimer Disease: genetics / tau Proteins:
                      metabolism / Animals / Humans / Mice / Proteomics / Mice,
                      Transgenic / Male / Disease Progression / Female / Brain:
                      metabolism / Brain: pathology / Aged / Cell Line, Tumor /
                      Phosphorylation / Disease Models, Animal / Aged, 80 and over
                      / Alzheimer’s disease (Other) / Mitochondrial dysfunction
                      (Other) / Protein aggregation (Other) / Proteomics (Other) /
                      Rapidly progressive Alzheimer’s disease (Other) / Tau
                      oligomers (Other) / tau Proteins (NLM Chemicals)},
      cin          = {AG Zerr / Clinical Dementia Research (Göttingen)},
      ddc          = {610},
      cid          = {I:(DE-2719)1440011-1 / I:(DE-2719)1440015},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41851356},
      doi          = {10.1007/s00401-026-02998-4},
      url          = {https://pub.dzne.de/record/285729},
}