TY - JOUR T1 - Misfolded Amyloid β-42 induced impairment of the endo-lysosomal pathway revealed by real-time optical monitoring JF - bioRxiv DO - 10.1101/598540 SP - 598540 AU - Karen E Marshall AU - Devkee Vadukul AU - Kevin Staras AU - Louise C Serpell Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/04/05/598540.abstract N2 - 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 significantly disrupts protein uptake. Our results identify a potential mechanism by which amyloidogenic aggregates directly impair cellular function through disruption of the endosomal-lysosomal pathway. ER -