NF-κB-Associated MnSOD Induction Protects Against β-Amyloid-Induced Neuronal Apoptosis

Abstract

Expression of manganese superoxide dismutase (MnSOD), a nuclear-encoded mitochondrial primary antioxidant enzyme, is protective against various paradigms of oxidative stress-induced brain injury. We have shown previously that the presence of an intronic nuclear factor site, kappaB (NF-kappaB), in the MnSOD gene is essential for the induction of MnSOD by tumor necrosis factor alpha (TNF-alpha). However, whether activation of NF-kappaB is protective against oxidative stress-induced neuronal injury is unclear. In the present study, we demonstrate that TNF-alpha activates NF-kappaB activity in neuronal, SH-SY5Y, cells and preferentially enhances the binding of p50 and p65 to the promoter/enhancer regions of the MnSOD gene. Binding of NF-kappaB members to the MnSOD gene leads to the induction of MnSOD mRNA and protein levels. Consequently, induction of MnSOD by TNF-alpha primes neuronal cells to develop resistance against subsequent exposure to beta-amyloid and FeSO(4). Taken together, these results suggest that NF-kappaB might exert its protective function by induction of MnSOD leading to subsequent protection against oxidative stress-induced neuronal injury.

Reactive Oxygen Species, Redox Signaling and Neuroinflammation in Alzheimer's Disease: The NF-κB Connection

“…In a related study the activation of NF-κB by a low dose of Aβ40 or Aβ25-35 involving ROS has been demonstrated in primary culture of neurons [89]. Consistent with the neuroprotective action of NF-κB activation, one study has reported that TNF-α treatment of SHSY5Y cells upregulates Mn-SOD gene through NF-κB activation which subsequently protects the cells from a challenge by amyloid beta peptide or ironmediated oxidative stress [101]. Another study identifies a resistant clone of PC12 cells against oxidative stress with constitutively high NF-κB activity [102].…”

FUsed in Sarcoma Is a Novel Regulator of Manganese Superoxide Dismutase Gene Transcription

“…However, the role of MnSOD in fALS pathogenesis remains elusive. MnSOD is expressed in almost all mammalian cells, including neurons, and can be induced under various conditions (10,16,37,50). We recently demonstrated that the molecular pathology of FUS mutation can be recapitulated in cell culture (20) and Drosophila (55) models.…”

Significant Improvements in Cognitive Performance Post-Transcranial, Red/Near-Infrared Light-Emitting Diode Treatments in Chronic, Mild Traumatic Brain Injury: Open-Protocol Study

“…Specific underlying physiological changes that occur post-LED therapy in this patient population are largely unknown. Data from animal and cellular studies, however, would suggest increase in ATP, 29,33,66,67 diffusion of nitric oxide promoting vasodilation 38 and rCBF in cortical areas, 31 an increase in antioxidants, 68 and decreased inflammation 39,69,70 as possible supporting mechanisms for improved function in the chronic stage. …”