NF-κB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid β-peptide toxicity

Abstract

Opposite effects of nuclear factor-jB (NF-jB) on neuron survival rely on activation of diverse NF-jB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1b. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-b (Ab), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Ab toxicity depends on cRel activation. Ab peptide induced NF-jB factors p50 and p65. The mGlu5 agonists activated c-Rel, besides p50 and p65, and the expression of manganese superoxide dismutase (MnSOD) and Bcl-X L . Targeting c-Rel expression by RNA interference suppressed the induction of both antiapoptotic genes. Targeting c-Rel or Bcl-X L prevented the prosurvival effect of mGlu5 agonists. Conversely, c-Rel overexpression or TATBcl-X L addition rescued neurons from Ab toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Reldependent antiapoptotic pathway responsible for neuroprotection against Ab peptide.

Bim and Noxa Are Candidates to Mediate the Deleterious Effect of the NF-κB Subunit RelA in Cerebral Ischemia

“…Nuclear fractions were isolated using commercially available reagents (Nuclear Extract Kit; Active Motif, Rixensart, Belgium). DNA binding activity of NF-B subunits p50, p65, c-Rel, p52, and RelB was monitored using a commercially available ELISA-based assay (TransFactor; BD Biosciences, Mountain View, CA) (Pizzi et al, 2005). Briefly, nuclear samples (3 g) were incubated in an ELISA plate coated with oligonucleotides containing an NF-B consensus regulatory element sequence.…”

“…Indeed, functional diversity is suggested by the unique phenotypes of knock-out mouse lines (Li and Verma, 2002). Recent evidence has shown that RelA exerts a proapoptotic and c-Rel an antiapoptotic effect in neurons (Pizzi et al, 2002(Pizzi et al, , 2005.…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Aside from a role in promoting neuronal survival (Pizzi et al, 2002(Pizzi et al, , 2005, c-Rel has also been implicated in long-term memory (LTM) formation. Consolidation of LTM requires N-methyl-D-aspartate receptor-dependent changes in gene expression.…”

NF‐κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress

“…Moreover, the c-Rel antisense made IL-1β exposure per se as toxic as the glutamate one (Pizzi et al, 2002). Further investigations confirmed that p50 and RelA subunit activation contributes to the apoptotic program in cells exposed to the β-amyloid peptide (Akama et al, 1998;Pizzi et al, 2005b;Valerio et al, 2006). In addition, the c-Rel-containing dimers p50/c-Rel and RelA/c-Rel are involved in neuroprotective effects elicited by S100B (Kögel et al, 2004), agonists at the metabotropic glutamate type 5 (mGlu5) receptors (Pizzi et al, 2005b;Sarnico et al, 2008b) or leptin (Valerio et al, 2009).…”