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

By Jennifer Chen, Yungui Zhou, Sarah Mueller-Steiner, Lin-Feng Chen, H. Kwon, Saili Yi, L. Mucke, L. Gan. Journal of Biological Chemistry, 2005

645 citations recorded by the source corpus.

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.

Subfields: Geriatrics and Gerontology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/2dd16f327edcdc1e3b1b964a72d2beb335eb8a34

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Citations in the corpus

Sirtuins in aging and age-related disease. (2006, background): “A final study related to neurodegeneration examined NF-κB signaling in microglia, an activity linked to amyloid-β neuronal death and Alzheimer’s disease, finding that overexpression of Sirt1 repressed NF-κB signaling by reducing RelA/p65 acetylation (Chen et al., 2005b).”
Acetylation of tau inhibits its degradation and contributes to tauopathy. (2010, positive): “Lentivirus was generated, purified, and used for infection as described (Chen et al., 2005).”
Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “Finally, ␤-amyloid-induced death of microglia is spared by overexpression of SIRT1 or resveratrol treatment (J. Chen et al. 2005).”
Astrocytes: Key Regulators of Neuroinflammation. (2016, background): “Accordingly, in vitro studies have shown that NFkB protects neurons against excitotoxic and metabolic insults [97], but it induces production of neurotoxic agents by other cell types such as microglia and astrocytes, thus leading to neuronal apoptosis indirectly [35,98].”
SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis (2007, background): “The SIRT1 gene is believed to provide cell protection during times of cell stress (Brunet et al, 2004; Cohen et al, 2004a, b; Chen et al, 2005; Tang, 2006).”
GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knock-in Mice (2009, methodology): “zygous apoE3-KI, apoE4-KI, wild-type, and apoE-KO mice (Chen et al., 2005) as described in Supplemental Data.”
Resveratrol improves health and survival of mice on a high-calorie diet (2006, neutral): “3)* Fasted IGF-I (ng ml(21)) 346 (40) 534 (12){ 482 (21){{ Fed 625 (33) 999 (102){ 929 (81){ Fasted IGFBP-1 (AU) 1.”
A network dysfunction perspective on neurodegenerative diseases (2006, background): “Notably, abnormal proteins can impair neurons indirectly through pathogenic glial loops involving the production of neurotoxic factors by microgli”