title: Lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity.
abstract: The 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion and free radicals formation characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. We suggested that AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70-80% of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding non-treated cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies.
authors.affiliation: Department of Cellular Signaling, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 02106 Warsaw, Poland.
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Strosznajder
authors.forename: Magdalena
authors.initials: M
authors.lastname: Cieslik
authors.forename: Magdalena
authors.initials: M
authors.lastname: Cakala
authors.forename: Henryk
authors.initials: H
authors.lastname: Jesko
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
authors.forename: Robert P
authors.initials: RP
authors.lastname: Strosznajder
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D058945:Lipoxygenases / Q000378:metabolism*; D016716:PC12 Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D058945:Lipoxygenases; D011065:Poly(ADP-ribose) Polymerases