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

The amyloid-beta (A{beta}) plaques found in Alzheimers disease (AD) patients brains contain collagens and are embedded extracellularly. Several collagens have been proposed to influence A{beta} 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 A{beta}1-42. This secreted A{beta} forms aggregates in two distinct places within the extracellular matrix. In a screen for extracellular human A{beta} aggregation regulators, we identified different collagens to ameliorate or potentiate A{beta} aggregation. We show that a disintegrin and metalloprotease ADM-2, an orthologue of ADAM9, reduces the load of extracellular A{beta} aggregates. ADM-2 is required and sufficient to remove the extracellular A{beta} aggregates. Thus, we provide in-vivo evidence of collagens essential for aggregate formation and metalloprotease participating in extracellular A{beta} aggregate removal. HighlightsExtracellular aggregates of amyloid beta are a hallmark of Alzheimers 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.