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

Opposite effects of nuclear factor-κB (NF-KB) on neuron survival rely on activation of diverse NF-κB factors. While p65 is necessary for glutamate-induced cell death, c-Rel mediates prosurvival effects of interleukin-1β. However, it is unknown whether activation of c-Rel-dependent pathways reduces neuron vulnerability to amyloid-β (Aβ), a peptide implicated in Alzheimer's disease pathogenesis. We show that neuroprotection elicited by activation of metabotropic glutamate receptors type 5 (mGlu5) against Aβ toxicity depends on c-Rel activation. Aβ peptide induced NF-κB 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 TAT-Bcl-X_L addition rescued neurons from Aβ toxicity. These data demonstrate that mGlu5 receptor activation promotes a c-Rel-dependent antiapoptotic pathway responsible for neuroprotection against Aβ peptide.