NF-kappaB factor c-Rel mediates neuroprotection elicited by mGlu5 receptor agonists against amyloid beta-peptide toxicity.
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.
Pizzi
M
M
Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, 25123 Brescia, Italy. pizzi@med.unibs.it
Sarnico
I
I
Boroni
F
F
Benarese
M
M
Steimberg
N
N
Mazzoleni
G
G
Dietz
G P H
GP
Bähr
M
M
Liou
H-C
HC
Spano
P F
PF
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D017353:Gene Deletion; D020868:Gene Silencing; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
C107349:2-chloro-5-hydroxyphenylglycine; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010648:Phenylacetates; D020569:Proto-Oncogene Proteins c-rel; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; C023010:4-hydroxyphenylglycine; D013482:Superoxide Dismutase; D005998:Glycine