Visualization of co-localization in A?42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death

Soura, Violetta, Stewart‑Parker, Maris, Williams, Thomas L., Ratnayaka, Arjuna, Atherton, Joe, Gorringe, Kirsti, Tuffin, Jack, Darwent, Elisabeth, Rambaran, Roma, Klein, William, Lacor, Pascale, Staras, Kevin, Thorpe, Julian and Serpell, Louise C. (2012) Visualization of co-localization in A?42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death. Biochemical Journal, 441 (2), 579-590. (doi:10.1042/BJ20110749). (PMID:21955321)

Abstract

A?42 [amyloid-? 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 A?42 oligomers to a neuroblastoma (SH-SY5Y) cell line results in a reduction in survival, and that A?42 enters the cells prior to cell death. Immunoconfocal and immunogold electron microscopy reveal the path of the A?42 with time through the endosomal system and shows that it accumulates in lysosomes. A 24 h incubation with A? results in cells that have damaged lysosomes showing signs of enzyme leakage, accumulate autophagic vacuoles and exhibit severely disrupted nuclei. Endogenous A? is evident in the cells and the results of the present study suggest that the addition of A? oligomers disrupts a crucial balance in A? conformation and concentration inside neuronal cells, resulting in catastrophic effects on cellular function and, ultimately, in cell death.

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Contributors

Author: Arjuna Ratnayaka

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