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Here, we overturn this paradigm by demonstrating that human phagocytic cells\u2014including differentiated THP-1 macrophages and iPSC-derived microglia\u2014are not merely passive responders but active producers of extracellular, seeding-competent A\u03b242 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, A\u03b242 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 A\u03b2 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.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>How amyloid plaques emerge and spread in Alzheimer\u2019s disease remains a critical unanswered question. Here, we show that human immune cells\u2014including brain-resident microglia\u2014can actively generate A\u03b242 fibrils, the form of amyloid most strongly linked to neurodegeneration. These cell-produced fibrils not only seed further amyloid buildup but also trigger tau aggregation, a key event in disease progression. We further demonstrate that genetic risk factors like TREM2 amplify this process. Our findings reveal a direct link between immune cell activity, genetic susceptibility, and the earliest stages of Alzheimer\u2019s pathology, offering new insights into disease mechanisms and potential intervention points.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.11.681781","type":"posted-content","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T03:10:22Z","timestamp":1760325022000},"source":"Crossref","is-referenced-by-count":1,"title":["Phagocytes as Plaque Catalysts: Human Macrophages Actively Generate Pathogenic A\u03b242 Fibrils with Seeding and Cross-Seeding Potency"],"prefix":"10.64898","author":[{"given":"Katerina","family":"Konstantoulea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meine","family":"Ramakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah C.","family":"Borrie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dries","family":"T\u2019syen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daan","family":"Moechars","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malgorzata A.","family":"Sliwinska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brajabandhu","family":"Pradhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Albertini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grigoria","family":"Tsaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"Houben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Fiers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3138-281X","authenticated-orcid":false,"given":"Dewilde","family":"Maarten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1036-1075","authenticated-orcid":false,"given":"Dietmar Rudolf","family":"Thal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"Michael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1346-8924","authenticated-orcid":false,"given":"Jonas J.","family":"Neher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5455-5819","authenticated-orcid":false,"given":"Bart","family":"De Strooper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9189-7399","authenticated-orcid":false,"given":"Frederic","family":"Rousseau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2020-0168","authenticated-orcid":false,"given":"Joost","family":"Schymkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101510051272000_2025.10.11.681781v1.1","unstructured":"Alzheimer\u2019s, A. 2019 Alzheimer\u2019s disease facts and figures includes a special report on Alzheimer\u2019s detection in the primary care setting: connecting patients and physicians. 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