SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling.
Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappaB signaling in microglia is critically involved in neuronal death induced by amyloid-beta (Abeta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappaB signaling in microglia by expression of the nondegradable IkappaBalpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappaB signaling in mediating Abeta toxicity. Stimulation of microglia with Abeta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappaB pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappaB signaling in Abeta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.
Chen
Jennifer
J
Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Zhou
Yungui
Y
Mueller-Steiner
Sarah
S
Chen
Lin-Feng
LF
Kwon
Hakju
H
Yi
Saili
S
Mucke
Lennart
L
Gan
Li
L
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002478:Cells, Cultured; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D008239:Lysine / Q000737:chemistry; D017628:Microglia / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D013267:Stilbenes; D049452:Green Fluorescent Proteins; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D001973:Bromodeoxyuridine; D008239:Lysine; D000077185:Resveratrol