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

J Biol Chem. 2005 Dec 2;280(48):40364-74. doi: 10.1074/jbc.M509329200. Epub 2005 Sep 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Animals
  • Bromodeoxyuridine / pharmacology
  • Cells, Cultured
  • Genes, Reporter
  • Genetic Vectors
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Lentivirus / genetics
  • Lysine / chemistry
  • Microglia / metabolism*
  • Microscopy, Fluorescence
  • Models, Biological
  • Models, Genetic
  • NF-kappa B / metabolism*
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Resveratrol
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Sirtuin 1
  • Sirtuins / metabolism
  • Sirtuins / physiology*
  • Stilbenes / pharmacology


  • Amyloid beta-Peptides
  • NF-kappa B
  • Stilbenes
  • Green Fluorescent Proteins
  • Sirt1 protein, rat
  • Sirtuin 1
  • Sirtuins
  • Bromodeoxyuridine
  • Lysine
  • Resveratrol