TY - JOUR
T1 - Depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in mouse cortical culture
AU - Ahn, Young Ho
AU - Kim, Yang Hee
AU - Hong, Seung Hwan
AU - Koh, Jae Young
N1 - Funding Information:
This study was supported by the Creative Research Initiatives from Korea Ministry of Science and Technology (J.Y.K.).
PY - 1998/11
Y1 - 1998/11
N2 - The central nervous system (CNS) contains a large amount of zinc; a substantial fraction of it is located inside synaptic vesicles of glutamatergic terminals in chelatable forms and released in a calcium- dependent manner with intense neuronal activity. Recently, it has been shown that excessive zinc influx can kill neurons in rats subjected to transient forebrain ischemia. On the other hand, severe depletion of zinc has been also reported to induce cell death in certain nonneuronal cells. Since decreases in tissue zinc have been associated with Alzheimer's disease (AD) and senile macular degeneration, we examined whether depletion of intracellular zinc with a zinc chelator can directly induce neuronal death in mouse cortical cultures. Exposure of cortical cultures to a cell-permeant zinc-chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 0.5-3.0 μM) induced gradually developing neuronal degeneration accompanied by various features of apoptosis: cell body shrinkage, nuclear condensation and fragmentation, and internucleosomal DNA breakage. At higher concentrations, TPEN induced additional glial cell death. TPEN-induced cell death was completely blocked by coaddition of zinc. Addition of a protein synthesis inhibitor cycloheximide as well as a caspase inhibitor carbobenzoxy-valyl- alanyl-aspartyl-fluoromethyl ketone (zVAD-fmk) markedly attenuated TPEN- induced neuronal death. On the other hand, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), phorbol 12-myristate 13- acetate (PMA), high K+, or an antioxidant, trolox, did not show any protective effect. The present results demonstrated that depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in cortical culture. Combined with the findings that extracellular zinc may promote extracellular β-amyloid (Aβ) aggregation and that total tissue zinc is reduced in AD, present results suggest a possibility that redistribution of zinc from intracellular to extracellular space may synergistically contribute to neuronal apoptosis in AD.
AB - The central nervous system (CNS) contains a large amount of zinc; a substantial fraction of it is located inside synaptic vesicles of glutamatergic terminals in chelatable forms and released in a calcium- dependent manner with intense neuronal activity. Recently, it has been shown that excessive zinc influx can kill neurons in rats subjected to transient forebrain ischemia. On the other hand, severe depletion of zinc has been also reported to induce cell death in certain nonneuronal cells. Since decreases in tissue zinc have been associated with Alzheimer's disease (AD) and senile macular degeneration, we examined whether depletion of intracellular zinc with a zinc chelator can directly induce neuronal death in mouse cortical cultures. Exposure of cortical cultures to a cell-permeant zinc-chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 0.5-3.0 μM) induced gradually developing neuronal degeneration accompanied by various features of apoptosis: cell body shrinkage, nuclear condensation and fragmentation, and internucleosomal DNA breakage. At higher concentrations, TPEN induced additional glial cell death. TPEN-induced cell death was completely blocked by coaddition of zinc. Addition of a protein synthesis inhibitor cycloheximide as well as a caspase inhibitor carbobenzoxy-valyl- alanyl-aspartyl-fluoromethyl ketone (zVAD-fmk) markedly attenuated TPEN- induced neuronal death. On the other hand, brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), phorbol 12-myristate 13- acetate (PMA), high K+, or an antioxidant, trolox, did not show any protective effect. The present results demonstrated that depletion of intracellular zinc induces protein synthesis-dependent neuronal apoptosis in cortical culture. Combined with the findings that extracellular zinc may promote extracellular β-amyloid (Aβ) aggregation and that total tissue zinc is reduced in AD, present results suggest a possibility that redistribution of zinc from intracellular to extracellular space may synergistically contribute to neuronal apoptosis in AD.
KW - Alzheimer's disease
KW - Brain-derived neurotrophic factor
KW - Caspase
KW - Cycloheximide
KW - Metals
KW - Neuronal death
KW - TPEN
UR - http://www.scopus.com/inward/record.url?scp=0032212462&partnerID=8YFLogxK
U2 - 10.1006/exnr.1998.6931
DO - 10.1006/exnr.1998.6931
M3 - Article
C2 - 9875267
AN - SCOPUS:0032212462
SN - 0014-4886
VL - 154
SP - 47
EP - 56
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -