Role of lipoxygenases and poly(ADP-ribose) polymerase in amyloid beta cytotoxicity

• Autorzy: Cieslik M. , Strosznajder J.B. , Gajkowska B. , Strosznajder R.P.
• Języki publikacji: EN

Abstrakty

EN

The roles of 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the molecular processes evoked by 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 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. 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 nontreated with SNP 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. Supported by MS&HE grant NN40113938 and MRC statutory theme No 7.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2011
• Tom: 71
• Numer: 1
• Opis fizyczny: p.148

Twórcy

autor

Cieslik M.

• Mossakowski Medical Research Centre, Department of Cellular Signaling, Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder J.B.

• Mossakowski Medical Research Centre, Department of Cellular Signaling, Polish Academy of Sciences, Warsaw, Poland

autor

Gajkowska B.

• Mossakowski Medical Research Centre, Department of Cell Ultrastructure, Polish Academy of Sciences, Warsaw, Poland

autor

Strosznajder R.P.

• Mossakowski Medical Research Centre, Department of Neurosurgery, Polish Academy of Sciences, Warsaw, Poland