RT Journal Article
SR Electronic
T1 Co-Induction of p75<sup>NTR</sup> and p75<sup>NTR</sup>-Associated Death Executor in Neurons After Zinc Exposure in Cortical Culture or Transient Ischemia in the Rat
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9096
OP 9103
DO 10.1523/JNEUROSCI.20-24-09096.2000
VO 20
IS 24
A1 Jeong Ae Park
A1 Joo-Yong Lee
A1 Taka-Aki Sato
A1 Jae-Young Koh
YR 2000
UL http://www.jneurosci.org/content/20/24/9096.abstract
AB Recently, a 22 kDa protein termed p75NTR-associated death executor (NADE) was discovered to be a necessary factor for p75NTR-mediated apoptosis in certain cells. However, the possible role for p75NTR/NADE in pathological neuronal death has yet been undetermined. In the present study, we have examined this possibility in vivo and in vitro. Exposure of cortical cultures to zinc induced both p75NTR and NADE in neurons, whereas exposure to NMDA, ionomycin, iron, or H2O2 induced neither. In addition, zinc exposure increased neuronal NGF expression and its release into the medium. A function-blocking antibody of p75NTR (REX) inhibited association between p75NTR and NADE as well as neuronal death induced by zinc. Conversely, NGF augmented zinc-induced neuronal death. Caspase inhibitors reduced zinc-induced neuronal death, indicating that caspases were involved. Because reduction of NADE expression with cycloheximide or NADE antisense oligonucleotides attenuated zinc-induced neuronal death, NADE appears to contribute to p75NTR-induced cortical neuronal death as shown in other cells. Because zinc neurotoxicity may be a key mechanism of neuronal death after transient forebrain ischemia, we next examined this model. After ischemia, p75NTR and NADE were induced in degenerating rat hippocampal CA1 neurons. There was a close correlation between zinc accumulation and p75NTR/NADE induction. Suggesting the role of zinc here, injection of a metal chelator, CaEDTA, into the lateral ventricle completely blocked the induction of p75NTR and NADE. Our results suggest that co-induction of p75NTR and NADE plays a role in zinc-triggered neuronal death in vitro and in vivo.