title: Oligomer-specific Abeta toxicity in cell models is mediated by selective uptake.
abstract: Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. Previous studies show that aggregated Abeta 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 Abeta1-42 and demonstrate that Abeta1-42 oligomers readily enter both HeLa and differentiated SKNSH cells whereas fibrillar Abeta1-42 is not internalized. Oligomeric Abeta1-42 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 Abeta toxicity.
authors.affiliation: Neurogenetics Laboratory Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sidhartha M
authors.initials: SM
authors.lastname: Chafekar
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D004705:Endocytosis / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D012235:Rhodamines
chemical_list: D016229:Amyloid beta-Peptides; D006575:Heterocyclic Compounds, 3-Ring; D010446:Peptide Fragments; D012235:Rhodamines; C075222:amyloid beta-protein (1-42); C412715:tetramethylrosamine