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 (Aβ), but the specific intracellular compartments involved in Aβ secretion remain contentious. While lysosomes are typically associated with Aβ degradation, studies have also shown that lysosomes also serve as site of Aβ 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 Aβ 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 Aβ from neurons and highlight its potential as a target for therapeutic intervention in Alzheimer’s disease.