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

Cell Death Differ. 2005 Jul;12(7):761-72. doi: 10.1038/sj.cdd.4401598.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Gene Deletion
  • Gene Silencing
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Phenylacetates / pharmacology
  • Proto-Oncogene Proteins c-rel / deficiency
  • Proto-Oncogene Proteins c-rel / genetics
  • Proto-Oncogene Proteins c-rel / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Superoxide Dismutase / metabolism


  • 2-chloro-5-hydroxyphenylglycine
  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • NF-kappa B
  • Neuroprotective Agents
  • Phenylacetates
  • Proto-Oncogene Proteins c-rel
  • RNA, Small Interfering
  • Receptors, Metabotropic Glutamate
  • 4-hydroxyphenylglycine
  • Superoxide Dismutase
  • Glycine