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


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

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Available from: Yungui Zhou, Nov 20, 2015
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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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    ABSTRACT: The orphan nuclear receptor estrogen-related receptor α (ERRα; NR3B1) is a key metabolic regulator, but its function in regulating inflammation remains largely unknown. Here, we demonstrate that ERRα negatively regulates Toll-like receptor (TLR)-induced inflammation by promoting Tnfaip3 transcription and fine-tuning of metabolic reprogramming in macrophages. ERRα-deficient (Esrra(-/-)) mice showed increased susceptibility to endotoxin-induced septic shock, leading to more severe pro-inflammatory responses than control mice. ERRα regulated macrophage inflammatory responses by directly binding the promoter region of Tnfaip3, a deubiquitinating enzyme in TLR signaling. In addition, Esrra(-/-) macrophages showed an increased glycolysis, but impaired mitochondrial respiratory function and biogenesis. Further, ERRα was required for the regulation of NF-κB signaling by controlling p65 acetylation via maintenance of NAD(+) levels and sirtuin 1 activation. These findings unravel a previously unappreciated role for ERRα as a negative regulator of TLR-induced inflammatory responses through inducing Tnfaip3 transcription and controlling the metabolic reprogramming. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 07/2015; 43(1-1):80-91. DOI:10.1016/j.immuni.2015.07.003 · 21.56 Impact Factor
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    • "An intersection between the sirtuin family of deacetylase proteins and NF-kB transcription factors occuring via the SIRT6 member of the family (Kawahara et al., 2009). There is a growing body of evidence about functional interrelationships between SIRT1 and NF-␬B and SIRT1 is one of the regulatory proteins of transcription factor NF-␬B. SIRT1 inhibits the transactivation potential of NF-␬B through deacetylation (Yeung et al., 2004; Chen et al., 2005; Yang et al., 2007; Bourguignon et al., 2009; Lee et al., 2009) and can inhibit NF-␬B-mediated transcription (Ghosh et al., 2007). It remains unknown whether SIRT1 can regulate the expression of different NF-␬B subunits and the interrelationships between SIRT1 and NF-␬B in the control of ovarian cell proliferation and secretory activity have not been studied. "
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    • "The effects of glucose deprivation were partially reversed by the addition of SIRT1 inhibitor (Fig. 2A and B). These data are consistent with those of previous studies (Yeung et al., 2004; Chen et al., 2005). Next, we investigated whether SIRT1 activation affects ROS production in astrocytes. "
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