Replicating neuroblastoma cells in different cell cycle phases display different vulnerability to amyloid toxicity.
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 Abeta1-40/42 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.
Cecchi
Cristina
C
Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy. cristina.cecchi@unifi.it
Pensalfini
Anna
A
Stefani
Massimo
M
Baglioni
Serena
S
Fiorillo
Claudia
C
Cappadona
Silvia
S
Caporale
Roberto
R
Nosi
Daniele
D
Ruggiero
Marco
M
Liguri
Gianfranco
G
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002784:Cholesterol