Neuroglobin attenuates β-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo

Abstract

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 ␤-amyloid (A␤) 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 A␤(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 ؋ APP Sw,Ind) mice showed reductions in thioflavin-S-stained extracellular A␤ deposits, decreased levels of A␤(1-40) and A␤(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 A␤ 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.globin ͉ lipid raft ͉ neurodegeneration ͉ neuroprotection ͉ NMDA N euroglobin (Ngb) is a vertebrate globin that is localized to neurons, binds O 2 and other gaseous messengers, is transcriptionally induced by hypoxia and ischemia, and protects against hypoxic neuronal death and ischemic brain injury (1). However, the mechanism through which Ngb exerts its neuroprotective effect is unclear. We found recently that hypoxia induces polarization of plasma membrane lipid microdomains (rafts) that appear to mediate hypoxic neuronal death because inhibiting their formation enhances survival of hypoxic neurons (A.A.K., unpublished data). Moreover, raft polarization precedes caspase activation and mitochondrial release of cytochrome c, indicating that it is an earlyand, thus, potentially reversible-event in cell-death pathways. Neurons from Ngb-overexpressing transgenic (Ngb-Tg) mice (2, 3) do not undergo membrane polarization in response to hypoxia and are resistant to hypoxic cell death, suggesting that Ngb may protect neurons from hypoxia by interfering with this cell-death signaling complex.In addition to its protective effects against neuronal hypoxia in vitro and cerebral ischemia in vivo, Ngb also reduces oxidative injury from H 2 O 2 or paraquat (4) and ␤-amyloid (A␤)-induced toxicity (5) in cultured neural cell lines. To determine whether inhibition of membrane polarization-dependent neuronal death by Ngb extends to insults other than hypoxia, we investigated the effect of transgenic overexpression of Ngb on the neuronal toxicity of the excitatory amino acid, NMDA, and the Alzheimer's disease (AD)-related peptide, A␤. Compartmentalization by ...

What is the function of neuroglobin?

“…In fact, it has been demonstrated that experimentally decreased Ngb levels reduced, whereas overexpression of Ngb improved survival of cultured neurons (Liu et al, 2009;Sun et al, 2001) or isolated islet of Langerhans cells (Mendoza et al, 2005). Ngb may also protect neurons from β-amyloid-induced neurotoxicity and thus from Alzheimer's disease (Khan et al, 2007). Mice over-expressing Ngb in the brain showed reduced tissue infarction and improved pathology after ischemia (Khan et al, 2006;Sun et al, 2003;Wang et al, 2008).…”

Silencing neuroglobin enhances neuronal vulnerability to oxidative injury by down-regulating 14-3-3γ

“…The expression of Ngb in most areas of the brain does not colocalize with neuronal nitric oxide synthase [9] . In Ngb-transgenic mice, the expression of endothelial nitric oxide synthase increases [10] . Therefore, determining whether NO-scavenging is an important physiological function of Ngb in the brain requires further study.…”

Ligand migration through the internal hydrophobic cavities in human neuroglobin

“…Ngb was shown to play a role in brain recovery from stroke (5) and transgenic mice overexpressing Ngb proved more resilient to experimentally induced cerebral and myocardial ischemia (6). Cultured neuronal cells from transgenic mice overexpressing Ngb showed a decreased beta-amyloid toxicity (7), suggesting a potential inhibiting role of Ngb in the onset of Alzheimer's disease.…”