When the brain’s cleanup crew helps build Alzheimer’s plaques

Microglia and related phagocytic cells are increasingly recognized as having a dual role in Alzheimer’s disease. Beyond clearing amyloid, they can also help shape how plaques form and evolve. In this study, we show that human phagocytic cells, including differentiated THP-1 macrophages and stem-cell-derived microglia, can actively convert soluble Aβ42 into extracellular fibrils, the amyloid species most closely linked to parenchymal plaque formation and neurodegeneration. This places innate immune cells not just around plaques, but directly within the earliest steps of amyloid assembly.

We further show that these cell-generated fibrils are not simply a cellular version of standard lab-made amyloid. They are structurally and functionally distinct, with markedly stronger biological activity: fibrils produced by THP-1 cells display a 12-fold higher Aβ seeding potency than cell-free fibrils and an 11-fold increase in tau cross-seeding in biosensor assays. Importantly, this is an active cellular process. Amyloid deposition depends on living phagocytic cells, is strongly reduced in fixed or non-phagocytic controls, and becomes even more pronounced when TREM2 function is impaired, linking a major Alzheimer’s risk pathway to the generation of especially pathogenic amyloid assemblies.

Together, these findings strengthen the idea that phagocytes do more than respond to amyloid after plaques appear. Under specific conditions, they can actively influence which Aβ42 assemblies emerge, how effectively those assemblies propagate, and how strongly amyloid pathology connects to tau dysfunction. By coupling human cell biology, genetic risk, and seeding-competent fibril formation in one experimentally accessible system, this work provides a new framework for studying early amyloid-immune interactions in Alzheimer’s disease and opens a human-relevant platform for mechanistic studies and therapeutic exploration.

Read the full paper here.