Phagocytes as Plaque Catalysts: Human Macrophages Actively Generate Pathogenic Aβ42 Fibrils with Seeding and Cross-Seeding Potency
Year: 2025
Type: preprint
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 iPSC-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, exhibiting heightened seeding activity and the ability to cross-seed tau aggregation, a key driver of AD progression. Notably, Aβ42 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 Aβ 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. Significance Statement How amyloid plaques emerge and spread in Alzheimer’s disease remains a critical unanswered question. Here, we show that human immune cells—including brain-resident microglia—can actively generate Aβ42 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’s pathology, offering new insights into disease mechanisms and potential intervention points.
Authors: Katerina Konstantoulea, Meine Ramakers, Sarah C. Borrie, Dries T’syen, Daan Moechars, Malgorzata A. Sliwinska, Brajabandhu Pradhan, Giulia Albertini, Grigoria Tsaka, Bert Houben, Mark Fiers, Dewilde Maarten, Dietmar Rudolf Thal, Willem Michael, Jonas J. Neher, Bart De Strooper, Frederic Rousseau, Joost Schymkowitz
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Risk factors for neuropathological hallmark lesions and cell death in preclinical and symptomatic Alzheimer’s disease: a chance for age-of-onset prediction?, Heterotypic aggregation of Aβ42 with disease-relevant proteins in Alzheimer’s disease, Heterotypic amyloid interactions as modulators of selective cellular vulnerability, G491962258, The role of protein aggregate maturation in Alzheimer's disease and other neurodegenerative disorders and its potential for disease monitoring and differential diagnosis., Structural and morphological studies of heterotypic amyloid fibrils, Heterotypic amyloid interactions as modulators of selective cellular vulnerability
OpenAlex ID: W4415096333