SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling

• Published in: The Journal of biological chemistry Vol. 280; no. 48; p. 40364
• Main Authors: Jennifer Chen, Yungui Zhou, Sarah Mueller-Steiner, Lin-Feng Chen, Hakju Kwon, Saili Yi, Lennart Mucke, Li Gan
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 02.12.2005
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M509329200

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