TY - JOUR
T1 - Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo
AU - Khan, Adil A.
AU - Xiao, Ou Mao
AU - Banwait, Surita
AU - Jin, Kunlin
AU - Greenberg, David A.
PY - 2007/11/27
Y1 - 2007/11/27
N2 - Neuroglobin (Ngb), a vertebrate globin expressed primarily in neurons, is induced by and protects against neuronal hypoxia and cerebral ischemia. To investigate the spectrum and mechanism of Ngb's neuroprotective action, we studied the effect of transgenic overexpression of Ngb on NMDA and β-amyloid (Aβ) toxicity in murine cortical neuron cultures in vitro and on the phenotype of Alzheimer's disease (AD) transgenic (APP Sw,Ind) mice. Compared with cortical neuron cultures from wild-type mice, cultures from Ngb-overexpressing transgenic (Ngb-Tg mice) were resistant to the toxic effects of NMDA and Aβ(25-35), as measured by polarization of cell membrane lipid rafts, mitochondrial aggregation, lactate dehydrogenase release, and nuclear fragmentation. In addition, compared with APP Sw,Ind mice, double-transgenic (Ngb-Tg x APPSw,Ind) mice showed reductions in thioflavin-S-stained extracellular Aβ deposits, decreased levels of Aβ(1-40) and Aβ(1-42), and improved behavioral performance in a Y-maze test of spontaneous alternations. These findings suggest that the spectrum of Ngb's neuroprotective action extends beyond hypoxic-ischemic insults. Ngb may protect neurons from NMDA and Aβ toxicity by inhibiting the formation of a death-signaling membrane complex, and interventions that increase Ngb expression could have therapeutic application in AD and other neurodegenerative disorders.
AB - Neuroglobin (Ngb), a vertebrate globin expressed primarily in neurons, is induced by and protects against neuronal hypoxia and cerebral ischemia. To investigate the spectrum and mechanism of Ngb's neuroprotective action, we studied the effect of transgenic overexpression of Ngb on NMDA and β-amyloid (Aβ) toxicity in murine cortical neuron cultures in vitro and on the phenotype of Alzheimer's disease (AD) transgenic (APP Sw,Ind) mice. Compared with cortical neuron cultures from wild-type mice, cultures from Ngb-overexpressing transgenic (Ngb-Tg mice) were resistant to the toxic effects of NMDA and Aβ(25-35), as measured by polarization of cell membrane lipid rafts, mitochondrial aggregation, lactate dehydrogenase release, and nuclear fragmentation. In addition, compared with APP Sw,Ind mice, double-transgenic (Ngb-Tg x APPSw,Ind) mice showed reductions in thioflavin-S-stained extracellular Aβ deposits, decreased levels of Aβ(1-40) and Aβ(1-42), and improved behavioral performance in a Y-maze test of spontaneous alternations. These findings suggest that the spectrum of Ngb's neuroprotective action extends beyond hypoxic-ischemic insults. Ngb may protect neurons from NMDA and Aβ toxicity by inhibiting the formation of a death-signaling membrane complex, and interventions that increase Ngb expression could have therapeutic application in AD and other neurodegenerative disorders.
KW - Globin
KW - Lipid raft
KW - NMDA
KW - Neurodegeneration
KW - Neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=37649003389&partnerID=8YFLogxK
U2 - 10.1073/pnas.0706167104
DO - 10.1073/pnas.0706167104
M3 - Article
C2 - 18025470
AN - SCOPUS:37649003389
SN - 0027-8424
VL - 104
SP - 19114
EP - 19119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 48
ER -