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@ARTICLE{Konstantoulea:285453,
      author       = {Konstantoulea, Katerina and Ramakers, Meine and Borrie,
                      Sarah C and T'Syen, Dries and Moechars, Daan and Sliwinska,
                      Malgorzata A and Pradhan, Brajabandhu and Albertini, Giulia
                      and Baligács, Nóra and Tsaka, Grigoria and Houben, Bert
                      and Fiers, Mark and Gallardo, Rodrigo and Dewilde, Maarten
                      and Thal, Dietmar Rudolf and Willem, Michael and Neher,
                      Jonas J and De Strooper, Bart and Rousseau, Frederic and
                      Schymkowitz, Joost},
      title        = {{P}hagocytes as plaque catalysts: {H}uman macrophages
                      generate seeding-competent {A}β42 fibrils with
                      cross-seeding activity.},
      journal      = {Proceedings of the National Academy of Sciences of the
                      United States of America},
      volume       = {123},
      number       = {10},
      issn         = {0027-8424},
      address      = {Washington, DC},
      publisher    = {National Acad. of Sciences},
      reportid     = {DZNE-2026-00235},
      pages        = {e2516774123},
      year         = {2026},
      abstract     = {The prevailing view frames microglia and macrophages as
                      guardians against amyloid beta (Aβ) accumulation in
                      Alzheimer's disease (AD). Here, we overturn this paradigm by
                      demonstrating that human phagocytic cells, including
                      differentiated THP-1 macrophages and hESC-derived microglia,
                      are not merely passive responders but active producers of
                      extracellular, seeding-competent Aβ42 fibrils, the amyloid
                      species most strongly linked to parenchymal plaque formation
                      and neurodegeneration. These cell-generated aggregates
                      differ structurally and functionally from synthetic fibrils,
                      displaying enhanced seeding and tau cross-seeding activity
                      in biosensor models. Notably, Aβ42 fibril formation in this
                      system requires active cellular processes and is exacerbated
                      by loss of Triggering Receptor Expressed on Myeloid Cells 2
                      (TREM2), a major AD risk gene. Transcriptomic profiling
                      reveals an early inflammatory response resembling microglial
                      states observed in human AD models. Together, these findings
                      support emerging evidence from in vivo studies that
                      macrophages and microglia can influence amyloid seeding and
                      introduce a human-relevant in vitro platform to explore how
                      Aβ aggregation intersects with innate immune function and
                      genetic risk. Our results reinforce the concept that
                      microglia may play a dual role in AD, acting both as
                      responders and inadvertent facilitators of amyloid assembly,
                      with implications for early therapeutic intervention.},
      keywords     = {Ab42 (Other) / Alzheimer’s disease (Other) / TREM2
                      (Other) / microglia (Other)},
      cin          = {AG Neher (München)},
      ddc          = {500},
      cid          = {I:(DE-2719)1110011},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41770935},
      doi          = {10.1073/pnas.2516774123},
      url          = {https://pub.dzne.de/record/285453},
}