MITOCHONDRIAL AND NUCLEAR TARGETS OF AMYLOID beta -EVOKED OXIDATIVE STRESS

Amyloid beta (A beta ) is responsible for mitochondrial failure and biochemical alterations linked to Alzheimer's disease (AD). To better understand mechanisms of A beta toxicity we investigated its mitochondrial and nuclear targets, apoptosis-inducing factor (AIF) and Poly(ADP-ribose) polymerase-1 (PARP-1) in PC12 cells transfected with wild type (APPwt) or double Swedish-mutated human Amyloid Precursor Protein gene (APPsw) characterized by different A beta concentrations. We found close relationship between A beta level and cyclooxygenase (COX)- and lipoxygenase (LOX)-related free radical formation leading to p65/NF- Kappa B nuclear translocation. COX and LOX inhibitors protected APPsw cells against p65 translocation. A beta -evoked oxidative stress enhanced mitochondrial AIF level and inhibited PARP-1 in APPsw cells. Nitrosative stress evoked by 0.5 mM sodium nitroprusside (SNP) had no further effect on A beta -altered PARP-1 activity and mitochondrial AIF level in APPsw cells. However, SNP evoked death of 70-80% of all cell types after 24 h. COX and LOX inhibitors had ameliorating effect in these conditions. Our data indicated that double Swedish mutation in APP significantly increased cell vulnerability to oxidative stress. Enhanced mitochondrial AIF level and PARP-1 inhibition might be responsible for cell survival under oxidative stress evoked by accumulating A beta in APPsw cells. COX and LOX inhibitors protected the cells against death caused by simultaneous A beta toxicity and nitrosative stress.