Neuroglobin protects PC12 cells against β-amyloid-induced cell injury

Abstract

Excessive accumulation of amyloid beta (Abeta) has been proposed as a pivotal event in the pathogenesis of Alzheimer's disease. Possible mechanisms underlying Abeta-induced neuronal cytotoxicity include excess production of reactive oxidative species (ROS) and apoptosis. Neuroglobin (Ngb), a newly discovered globin in vertebrates that exhibits neuroprotective functions, may have a potential role in scavenging ROS. To examine the potential protective role of Ngb in Abeta-induced cytotoxicity, PC12 cells were treated with Abeta (1-42 fragment) for 24h. Abeta treatments increased ROS production in PC12 cells. Overexpression of Ngb but not Ngb mutant in the PC12 cells significantly attenuated Abeta-induced ROS production and lipids peroxidation. Furthermore, overexpression of Ngb also attenuated Abeta-induced mitochondrial dysfunction and apoptosis, and promoted cell survival in PC12 cells. Therefore, Ngb may act as an intracellular ROS scavenger, and such antioxidant properties may play a protective role against Abeta-induced cell injury.

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

“…Although Ngb binds O 2 , enhanced O 2 delivery is considered unlikely to explain its protective effect against hypoxic or ischemic injury because its intraneuronal concentration (Ϸ1 M) is too low to account for appreciable changes in intracellular O 2 levels (1). In addition, Ngb appears to reduce neuronal death from other than hypoxic or ischemic insults (4,5). Consequently, alternative protective mechanisms have been proposed, including scavenging of reactive oxygen or nitrogen species (23) and promoting the dissociation of G protein ␤␥ subunits (24) that activate antiapoptotic pathways (25).…”

“…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␤.…”

Neuroglobin protects against nitric oxide toxicity

“…In addition, Ngb-overexpressing transgenic mice are resistant to cerebral infarction from occlusion of the middle cerebral artery [10,11]. Ngb also reduces the toxicity of H 2 O 2 [5], paraquat [5] and β-amyloid [13] in vitro. However, the mechanisms that underlie neuroprotection by Ngb are unknown.…”

“…In addition, Ngb appears to reduce neuronal death from other insults besides hypoxia or ischemia [5,13]. Consequently, alternative protective mechanisms have been proposed, including scavenging of reactive oxygen or nitrogen species [1] and promoting the dissociation of G-protein βγ subunits [26] that activate antiapoptotic pathways [19].…”

A role for human neuroglobin in apoptosis

“…Experimentally, in cultured cells, over expression of neuroglobin protects against amyloid beta, hydrogen peroxide, paraquat, and HA14-1 (a Bcl-2 inhibitor) induced cell death, as well as from oxygen and glucose deprivation (16)(17)(18)(19)(20)(21). In vitro, knockdown of endogenous neuroglobin renders cortical neurons more susceptible to hypoxia (16), and decreases viability of neuroblastoma cells under oxidative stress (22).…”