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

Jennifer Chen, Yungui Zhou, Sarah Mueller-Steiner, Lin Feng Chen, Hakju Kwon, Saili Yi, Lennart Mucke, Li Gan

Research output: Contribution to journalArticlepeer-review

Abstract

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 SIRTl deacetylase and the addition of the SIRTl 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 SIRTl in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.

Original languageEnglish (US)
Pages (from-to)40364-40374
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number48
DOIs
StatePublished - Dec 2 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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