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The Journal of Neuroscience, December 15, 2000, 20(24):9096-9103

Co-Induction of p75^NTR and p75^NTR-Associated Death Executor in Neurons After Zinc Exposure in Cortical Culture or Transient Ischemia in the Rat

Jeong Ae Park¹, Joo-Yong Lee¹, Taka-Aki Sato^{2, 3}, and Jae-Young Koh¹

¹ National Creative Research Initiative Center for the Study of CNS Zinc and Department of Neurology, University of Ulsan College of Medicine, 388-1 Poongnap-Dong Songpa-Gu, Seoul 138-736, Korea, ² Molecular Oncology Laboratory, Tsukuba Life Science Center, Institute of Physical and Chemical Research (RIKEN), Ibaraki 305-0074, Japan, and ³ Division of Molecular Oncology, Department of Otolaryngology, Head and Neck Surgery and Pathology, College of Physicians and Surgeons, Columbia University, New York, New York 10032

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 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 p75^NTR 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 p75^NTR (REX) inhibited association between p75^NTR 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 p75^NTR-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, p75^NTR and NADE were induced in degenerating rat hippocampal CA1 neurons. There was a close correlation between zinc accumulation and p75^NTR/NADE induction. Suggesting the role of zinc here, injection of a metal chelator, CaEDTA, into the lateral ventricle completely blocked the induction of p75^NTR and NADE. Our results suggest that co-induction of p75^NTR and NADE plays a role in zinc-triggered neuronal death in vitro and in vivo.

Key words: neurotrophin; nerve growth factor; apoptosis; caspase; TFL-Zn; calcium; oxidative injury

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20249096-08$05.00/0

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