Phagocytes as Plaque Catalysts: Human Macrophages Generate Seeding-Competent Aß42 Fibrils with Cross-Seeding Activity

The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aß) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells—including differentiated THP-1 macrophages and iPSC-derived microglia—are not merely passive responders but active producers of extracellular, seeding-competent Aß42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, exhibiting heightened seeding activity and the ability to cross-seed tau aggregation, a key driver of AD progression. Notably, Aß42 fibril formation in this system requires active cellular processes and is exacerbated by loss of TREM2, a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models, positioning this system as a tractable, human-relevant platform to dissect the interplay between Aß aggregation, innate immunity, and genetic susceptibility. Our findings suggest that macrophages and microglia play a dual role in AD, acting both as responders and inadvertent catalysts of pathogenic amyloid formation, with implications for early therapeutic intervention. Overall design: RNA-seq profiling of THP-1 Macrophages exposed to different levels of Aß42 peptide