1. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling
- Author
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Saili Yi, Li Gan, Lin Feng Chen, Yungui Zhou, Lennart Mucke, Jennifer Y. Chen, Sarah Mueller-Steiner, and Hakju Kwon
- Subjects
Genetic Vectors ,Green Fluorescent Proteins ,Resveratrol ,Biochemistry ,Neuroprotection ,Models, Biological ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Sirtuin 1 ,Alzheimer Disease ,Genes, Reporter ,Stilbenes ,medicine ,Animals ,Humans ,Sirtuins ,Molecular Biology ,Cells, Cultured ,Neurons ,Amyloid beta-Peptides ,Microglia ,biology ,Models, Genetic ,Reverse Transcriptase Polymerase Chain Reaction ,Lysine ,Neurodegeneration ,Lentivirus ,Neurotoxicity ,NF-kappa B ,Cell Biology ,medicine.disease ,Immunohistochemistry ,Cell biology ,Rats ,IκBα ,medicine.anatomical_structure ,chemistry ,Bromodeoxyuridine ,Microscopy, Fluorescence ,Immunology ,biology.protein ,Signal transduction ,Signal Transduction - Abstract
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. more...
- Published
- 2005