Article

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

Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94158, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2006; 280(48):40364-74. DOI: 10.1074/jbc.M509329200
Source: PubMed

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 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.

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Available from: Yungui Zhou, Nov 20, 2015
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    • "The inhibitory effect of resveratrol and SIRT1 overexpression on the AII/AT1/NADPH-oxidase pathway was confirmed in primary mesencephalic cultures, in the dopaminergic neuron cell line MES 23.5 and in the N9 microglial cell line. Treatment with resveratrol induced a significant decrease in levels of AT1 and p47 phox , and this effect was blocked by the simultaneous treatment with the SIRT1 inhibitor EX527, which is consistent with the major role of SIRT1 in the inhibitory effects of resveratrol on the microglial response161718 51]. The exact mechanism responsible for the inhibitory effect of SIRT1 on the AII/AT1 pathway remains to be fully clarified. "
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    • "Consistent with this, ChIPqPCR data showed that several genes involved in glycolysis including Pdk4 (an inhibitor of the conversion of pyruvate to acetyl-CoA) and Slc2a1 (glucose transporter 1), was elevated in Esrra –/– BMDM compared with WT BMDM (Figure S2B, bottom). Sirtuin 1 (SIRT1) is an NAD + -dependent deacetylase that is critically involved in the regulation of NF-kB-mediated inflammatory responses via the deacetylation of p65/RelA on lysine 310 (Chen et al., 2005; Yang et al., 2012; Yang et al., 2006; Yeung et al., 2004). We evaluated the influence of ERRa on SIRT1-medi- ated deacetylation of NF-kB p65. "
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