SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling

Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappa B signaling in microglia is critically involved in neuronal death induced by amyloid-beta( A beta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappa B signaling in microglia by expression of the nondegradable I kappa B alpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappa B signaling in mediating A beta toxicity. Stimulation of microglia with A beta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappa B pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappa B signaling stimulated by A beta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappa B signaling in A beta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.