Oligomer-specific Aβ toxicity in cell models is mediated by selective uptake

Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded β-amyloid (Aβ) peptide. Previous studies show that aggregated Aβ is more toxic in oligomeric than in fibrillar form, and that each aggregation form activates specific molecular pathways in the cell. We hypothesize that these differences between oligomers and fibrils are related to their different accessibility to the intracellular space. To this end we used fluorescently labelled Aβ1–42 and demonstrate that Aβ1–42 oligomers readily enter both HeLa and differentiated SK‑N‑SH cells whereas fibrillar Aβ1–42 is not internalized. Oligomeric Aβ1–42 is internalized by an endocytic process and is transported to the lysosomes. Inhibition of uptake specifically inhibits oligomer but not fibril toxicity. Our study indicates that selective uptake of oligomers is a determinant of oligomer specific Aβ toxicity.