Removal of extracellular human amyloid beta aggregates by extracellular proteases in C. elegans

The amyloid-beta (Aβ) plaques found in Alzheimer’s disease (AD) patients’ brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence Aβ aggregate formation, yet their role in clearance is unknown. To investigate the potential role of collagens in forming and clearance extracellular aggregates in vivo , we created a transgenic Caenorhabditis elegans strain that expresses and secretes human Aβ 1-42 . This secreted Aβ forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human Aβ aggregation regulators, we identified different collagens to ameliorate or potentiate Aβ aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular Aβ aggregates. ADM-2 is required and sufficient to remove the extracellular Aβ aggregates. Thus, we provide in-vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular Aβ aggregate removal. Highlights Extracellular aggregates of amyloid beta are a hallmark of Alzheimer’s disease. Here we developed a novel C. elegans transgenic line that secretes human amyloid beta, which forms aggregates in the extracellular matrix (ECM). We show that ECM dynamics can disturb aggregation and that ADM-2, an ortholog of Human ADAM9, is involved in removing these extracellular aggregates.