Amyloid beta is released by lysosomal exocytosis from hiPSC-derived neurons

The endosomal-lysosomal system has long been linked to the production of amyloid beta (A{beta}), but the specific intracellular compartments involved in A{beta} secretion remain contentious. While lysosomes are typically associated with A{beta} degradation, studies have also shown that lysosomes also serve as site of A{beta} accumulation in cells, mouse models, and human tissues. Lysosomal exocytosis is a major secretory pathway in non-neuronal cells, but few studies have investigated this pathway in neurons. Here, we examined the potential role and mechanism of lysosomal exocytosis in human induced pluripotent stem cell (hiPSC)-derived neurons, and we hypothesized that lysosomal exocytosis is a pathway for A{beta} secretion from these neurons. Using total internal reflection fluorescence (TIRF) microscopy, lysosomes filled with fluorescently labelled amyloid were seen approaching and fusing with the plasma membrane in real-time. The number and composition of the released particles were characterized using nanoscale flow cytometry. Silencing two proteins, Rab27b and munc13-4, significantly reduced these events and blocked the release of amyloid into the extracellular space. Our results provide direct evidence for the involvement of lysosomal exocytosis in the release of A{beta} from neurons and highlight its potential as a target for therapeutic intervention in Alzheimers disease.