TY  - JOUR
AU  - Konstantoulea, Katerina
AU  - Ramakers, Meine
AU  - Borrie, Sarah C
AU  - T'Syen, Dries
AU  - Moechars, Daan
AU  - Sliwinska, Malgorzata A
AU  - Pradhan, Brajabandhu
AU  - Albertini, Giulia
AU  - Baligács, Nóra
AU  - Tsaka, Grigoria
AU  - Houben, Bert
AU  - Fiers, Mark
AU  - Gallardo, Rodrigo
AU  - Dewilde, Maarten
AU  - Thal, Dietmar Rudolf
AU  - Willem, Michael
AU  - Neher, Jonas J
AU  - De Strooper, Bart
AU  - Rousseau, Frederic
AU  - Schymkowitz, Joost
TI  - Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 123
IS  - 10
SN  - 0027-8424
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - DZNE-2026-00235
SP  - e2516774123
PY  - 2026
AB  - 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.
KW  - Ab42 (Other)
KW  - Alzheimer’s disease (Other)
KW  - TREM2 (Other)
KW  - microglia (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:41770935
DO  - DOI:10.1073/pnas.2516774123
UR  - https://pub.dzne.de/record/285453
ER  -