title: Visualization of co-localization in Aβ42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death.
abstract: Aβ42 [amyloid-β peptide-(1-42)] plays a central role in Alzheimer's disease and is known to have a detrimental effect on neuronal cell function and survival when assembled into an oligomeric form. In the present study we show that administration of freshly prepared Aβ42 oligomers to a neuroblastoma (SH-SY5Y) cell line results in a reduction in survival, and that Aβ42 enters the cells prior to cell death. Immunoconfocal and immunogold electron microscopy reveal the path of the Aβ42 with time through the endosomal system and shows that it accumulates in lysosomes. A 24 h incubation with Aβ results in cells that have damaged lysosomes showing signs of enzyme leakage, accumulate autophagic vacuoles and exhibit severely disrupted nuclei. Endogenous Aβ is evident in the cells and the results of the present study suggest that the addition of Aβ oligomers disrupts a crucial balance in Aβ conformation and concentration inside neuronal cells, resulting in catastrophic effects on cellular function and, ultimately, in cell death.
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, BN1 9QG, UK.
authors.forename: Violetta
authors.initials: V
authors.lastname: Soura
authors.forename: Maris
authors.initials: M
authors.lastname: Stewart-Parker
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Williams
authors.forename: Arjuna
authors.initials: A
authors.lastname: Ratnayaka
authors.forename: Joe
authors.initials: J
authors.lastname: Atherton
authors.forename: Kirsti
authors.initials: K
authors.lastname: Gorringe
authors.forename: Jack
authors.initials: J
authors.lastname: Tuffin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Darwent
authors.forename: Roma
authors.initials: R
authors.lastname: Rambaran
authors.forename: William
authors.initials: W
authors.lastname: Klein
authors.forename: Pascale
authors.initials: P
authors.lastname: Lacor
authors.forename: Kevin
authors.initials: K
authors.lastname: Staras
authors.forename: Julian
authors.initials: J
authors.lastname: Thorpe
authors.forename: Louise C
authors.initials: LC
authors.lastname: Serpell
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D001343:Autophagy / Q000502:physiology*; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002966:Clathrin / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000473:pathology; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002966:Clathrin; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C533922:CTSD protein, human; D002402:Cathepsin D