Replicating neuroblastoma cells in different cell cycle phases display different vulnerability to amyloid toxicity

Abstract

A key role of mitotic activation in neuronal cell death in early stages of Alzheimer’s disease (AD) has been suggested. Apparently, terminally differentiated neurons are precluded from mitotic division, yet some phenotypic markers of cell cycling are present in AD-vulnerable brain areas. In this paper, we investigated whether dividing human neuroblastoma cells are preferentially vulnerable to amyloid aggregate toxicity in some specific cell cycle stage(s). Our data indicate that Aβ1–40/42 aggregates added to the cell culture media bind to the plasma membrane and are internalized faster in the S than in the G2/M and G1 cells possibly as a result of a lower content in membrane cholesterol in the former. Earlier and sharper increases in reactive oxygen species production triggered a membrane oxidative injury and a significant impairment of antioxidant capacity, eventually culminating with apoptotic activation in S and, to a lesser extent, in G2/M exposed cells. G1 cells appeared more resistant to the amyloid-induced oxidative attack possibly because of their higher antioxidant capacity. The high vulnerability of S cells to aggregate toxicity extends previous data suggesting that neuronal loss in AD could result from mitotic reactivation of terminally differentiated neurons with arrest in the S phase.

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Acknowledgments

This study has been supported by grants from the Italian MIUR (project numbers 2005054147_001 and 2005053998_001) from the Ente Cassa di Risparmio di Firenze (ref. no. 2005.0701) and from the Compagnia di San Paolo, Torino, Italy (ref. no. 2004.0995). All authors declare the absence of any actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 2 years of beginning the work submitted that could inappropriately influence (bias) their work. All data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere, and will not be submitted elsewhere while under the consideration at the Journal of Molecular Medicine. All authors have reviewed the contents of the manuscript being submitted, approve of its contents, and validate the accuracy of the data.

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Correspondence to Cristina Cecchi.

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Cecchi, C., Pensalfini, A., Stefani, M. et al. Replicating neuroblastoma cells in different cell cycle phases display different vulnerability to amyloid toxicity. J Mol Med 86, 197–209 (2008). https://doi.org/10.1007/s00109-007-0265-3

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Keywords

  • Protein aggregation
  • Amyloid toxicity
  • Amyloid aggregates
  • Cell cycle
  • Apoptosis