SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling.

TitleSIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling.
Publication TypeJournal Article
Year of Publication2005
AuthorsChen J, Zhou Y, Mueller-Steiner S, Chen L-F, Kwon H, Yi S, Mucke L, Gan L
JournalJ Biol Chem
Date Published2005 Dec 02
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Bromodeoxyuridine, Cells, Cultured, Genes, Reporter, Genetic Vectors, Green Fluorescent Proteins, Humans, Immunohistochemistry, Lentivirus, Lysine, Microglia, Microscopy, Fluorescence, Models, Biological, Models, Genetic, Neurons, NF-kappa B, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sirtuin 1, Sirtuins, Stilbenes

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.

Alternate JournalJ. Biol. Chem.
PubMed ID16183991
Grant ListNS43945 / NS / NINDS NIH HHS / United States