Microglia initially seed and later reshape amyloid plaques in Alzheimer’s disease

We demonstrate the dual role of microglia in Alzheimer’s disease (AD), initially harmful, by seeding amyloid plaques, and protective in later stages by compacting amyloid plaques. Early microglial depletion using pharmacological or genetic blockage of CSF1R reduces plaque load and associated neuritic dystrophy, while human microglia transplantation restores plaque formation, confirming their seeding role. Transplanted TREM2R47H/R47Hmicroglia exacerbate plaque pathology, highlighting microglia as key initiators of the amyloid pathology cascade.