Lysosomes Mediate Rab27b-Dependent Secretion of Beta-Amyloid
Abstract
Extracellular deposition of beta-Amyloid (Aβ) is an early event in Alzheimer’s disease development. However, it is not known how Aβ is secreted. Lysosomes readily undergo calcium-dependent exocytosis, a process that relies on small GTPase Rab27b. In addition, lysosomal enzymes have been found within extracellular amyloid plaques. We hypothesized that lysosomes mediate Rab27b-dependent exocytosis of Aβ. Neuro-2a cells were transfected with wild-type or mutant Rab27b constructs and/or a lysosomal marker. Cells were incubated with Aβ monomers and imaged using a confocal microscope before and after stimulation of calcium-dependent exocytosis. We observed a significant decrease in lysosome and Aβ co-localization post-treatment in comparison to pre-treatment in control samples. We also observed a significant increase in lysosome and Aβ co-localization post-treatment in Rab27b dominant-negative mutants in comparison to control. These results demonstrate that lysosomes can mediate Rab27b-dependent exocytosis of Aβ, thus elucidating a mechanism by which Aβ could be secreted in Alzheimer’s disease.