Extracellular amyloid-β42 oligomers alter endo-lysosomal trafficking of Rab7- and Lamp-1-coated vesicles in cultured neuroblastoma cells.

BackgroundThe levels of soluble amyloid-β (Aβ)42 oligomers in the brains of patients with Alzheimer's disease (AD) are well-known to correlate with the extent of synaptic loss. However, the abnormal role of these oligomers in disrupting the balance of the endo-lysosomal pathways for substance degradation in AD brains and cellular models remains unclear.ObjectiveWe aimed to investigate whether extracellular Aβ42 oligomers alter the composition, distribution, and identity of vesicular components and impact the processing of substances involved in the endo-lysosomal pathways of protein degradation.MethodsWe overexpressed Rab7, Lamp-1, and β-1,4-galactosyltransferase-1 proteins in nondifferentiated SH-SY5Y cells. We then incubated these cells with extracellular Aβ42 oligomers, and evaluated the effects on the morphology, composition, and distribution of vesicular components in the endo-lysosomal pathway using super-resolution confocal microscopy. Additionally, we assessed the effects of Aβ42 oligomers incubation on the degradation and processing of endocytosed fluorescent transferrin in vivo.ResultsOur findings revealed that Aβ42 oligomers alter the distribution and identity of Rab7- and Lamp-1-coated vesicles, as well as the Golgi apparatus. This alteration resulted in the formation of disorganized vesicles carrying distinct surface markers of the endo-lysosomal pathway, without evident changes to the cytoskeleton. In vivo evaluation showed a delayed degradation of endocytosed fluorescent transferrin after incubation with Aβ42 oligomers.ConclusionsAβ42 oligomers may contribute to neuronal toxicity by inducing changes in the identity, distribution and balance of vesicular components associated with the endo-lysosomal pathway. This disruption impacts the processing and degradation of various materials that accumulate in the cytoplasm.