Extracellular amyloid-β ₄₂ 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.