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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    • "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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    ABSTRACT: Local angiotensin II (AII) and sirtuin 1 (SIRT1) play a major role in the modulation of neuroinflammation, oxidative stress and aging-related dopaminergic vulnerability to damage. However, it is not known whether the modulation is related to reciprocal regulation between SIRT1 and AII. In the present study, a single intraventricular injection of AII increased nigral SIRT1 levels in young adult rats. Although AII activity is known to be increased in aged rats, levels of SIRT1 were significantly lower than in young controls. Treatment with the SIRT1-activating compound resveratrol increased nigral SIRT1 levels in aged rats. Levels of SIRT1 were significantly higher in aged wild type mice than in AII type-1 receptor (AT1) deficient mice. In cell culture studies, treatment with AII also induced a transitory increase in levels of SIRT1 in the MES 23.5 dopaminergic neuron and the N9 microglial cell lines. In aged rats, treatment with resveratrol induced a significant decrease in the expression of AT1 receptors and markers of NADPH-oxidase activation (p47phox). In aged transgenic mice over-expressing SIRT1, levels of AT1 and p47 phox were lower than in aged wild type controls. In vitro, the inhibitory effects of resveratrol on AII/AT1/NADPH-oxidase activity were confirmed in primary mesencephalic cultures, the N9 microglial cell line, and the dopaminergic neuron cell line MES 23.5, and they were blocked by the SIRT1 specific inhibitor EX527. The present findings show that SIRT1 and the axis AII/AT1/NADPH-oxidase regulate each other. This is impaired in aged animals and may be mitigated with sirtuin-activating compounds.
    Full-text · Article · Sep 2015 · Oncotarget
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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.
    Full-text · Article · Jul 2015 · Immunity
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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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    ABSTRACT: The roles of the mTOR system enzyme sirtuin 1 (SIRT1), the transcription factor p53 and the nuclear factor kappaB (NF-κB) and their interrelationships in the control of ovarian function have not been well studied. We examine, in vitro, the involvement of SIRT1, p53 and the p65 and p50 subunits of NFκB and their interrelationships in the control of the apoptosis and proliferation of porcine ovarian granulosa cells. Monolayers of primary granulosa cells were transfected with cDNA constructs encoding SIRT1, p53, p65 or p50 alone or were co-transfected with gene constructs for SIRT1 together with p53, p65 or p50. The accumulation of SIRT1, markers of proliferation (mitogen-activated protein kinase or extracellular-signal-regulated kinases 1,2) and a marker of apoptosis (caspase 3) was detected by immunocytochemistry. Transfection of cells with a SIRT1 gene construct alone promoted the accumulation of SIRT1 and decreased the accumulation of proliferation markers but did not affect the marker of apoptosis. Transfection of cells with gene constructs encoding p53, p50 or p65 decreased the expression of proliferation markers but not the apoptosis marker. Co-transfection of cells with SIRT1 cDNA changed the action of p65 on cell proliferation from inhibitory to stimulatory. SIRT1 overexpression induced the pro-apoptotic action of p53 and p50 but not of p65 constructs. Thus, SIRT1, p53 and NF-κB are involved in the control of both the proliferation and the apoptosis of ovarian cells. These novel data on the cross-talk between the mTOR/SIRT1 system and the transcription factors p53 and NF-κB show both the inhibitory (proliferation) and stimulatory (apoptosis) influences of SIRT1 on transcription factor action in ovarian cells.
    Full-text · Article · Jul 2014 · Cell and Tissue Research
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