Misfolded amyloid-β-42 impairs the endosomal-lysosomal pathway

Cell Mol Life Sci. 2020 Dec;77(23):5031-5043. doi: 10.1007/s00018-020-03464-4. Epub 2020 Feb 5.


Misfolding and aggregation of proteins is strongly linked to several neurodegenerative diseases, but how such species bring about their cytotoxic actions remains poorly understood. Here we used specifically-designed optical reporter probes and live fluorescence imaging in primary hippocampal neurons to characterise the mechanism by which prefibrillar, oligomeric forms of the Alzheimer's-associated peptide, Aβ42, exert their detrimental effects. We used a pH-sensitive reporter, Aβ42-CypHer, to track Aβ internalisation in real-time, demonstrating that oligomers are rapidly taken up into cells in a dynamin-dependent manner, and trafficked via the endo-lysosomal pathway resulting in accumulation in lysosomes. In contrast, a non-assembling variant of Aβ42 (vAβ42) assayed in the same way is not internalised. Tracking ovalbumin uptake into cells using CypHer or Alexa Fluor tags shows that preincubation with Aβ42 disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates impair cellular function through disruption of the endosomal-lysosomal pathway.

Keywords: Amyloid-beta; Endocytosis; Lysosomes; Oligomer; Self-assembly; Toxicity.

MeSH terms

  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Cells, Cultured
  • Dynamins / metabolism
  • Endocytosis / drug effects
  • Endosomes / metabolism*
  • Endosomes / ultrastructure
  • Hydrogen-Ion Concentration
  • Lysosomes / drug effects
  • Lysosomes / metabolism*
  • Lysosomes / ultrastructure
  • Neurons / drug effects
  • Neurons / pathology
  • Ovalbumin / metabolism
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Peptide Fragments / toxicity
  • Protein Folding* / drug effects
  • Rats


  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Ovalbumin
  • Dynamins