NF-κB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid β-peptide toxicity
Cell Death and Differentiation
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)
... tors type 5 (mGlu5) against Ab toxicity depends on c-Rel 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 TAT-Bcl-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.