Co-induction of p75(NTR) and p75(NTR)-associated death executor in neuronsafter zinc exposure in cortical culture or transient ischemia in the rat

Recently, a 22 kDa protein termed p75(NTR)-associated death executor (NADE) was discovered to be a necessary factor for p75(NTR)-mediated apoptosis in certain cells. However, the possible role for p75(NTR)/NADE in pathologica l neuronal death has yet been undetermined. In the present study, we have e xamined this possibility in vivo and in vitro. Exposure of cortical culture s to zinc induced both p75(NTR) and NADE in neurons, whereas exposure to NM DA, ionomycin, iron, or H2O2 induced neither. In addition, zinc exposure in creased neuronal NGF expression and its release into the medium. A function -blocking antibody of p75(NTR) (REX) inhibited association between p75(NTR) and NADE as well as neuronal death induced by zinc. Conversely, NGF augmen ted zinc-induced neuronal death. Caspase inhibitors reduced zinc-induced ne uronal death, indicating that caspases were involved. Because reduction of NADE expression with cycloheximide or NADE antisense oligonucleotides atten uated zinc-induced neuronal death, NADE appears to contribute to p75(NTR)-i nduced cortical neuronal death as shown in other cells. Because zinc neurot oxicity may be a key mechanism of neuronal death after transient forebrain ischemia, we next examined this model. After ischemia, p75(NTR) and NADE we re induced in degenerating rat hippocampal CA1 neurons. There was a close c orrelation between zinc accumulation and p75(NTR)/NADE induction. Suggestin g the role of zinc here, injection of a metal chelator, CaEDTA, into the la teral ventricle completely blocked the induction of p75(NTR) and NADE. Our results suggest that coinduction of p75(NTR) and NADE plays a role in zinc- triggered neuronal death in vitro and in vivo.