Inhibition of NF-κB potentiates amyloid β-mediated neuronal apoptosis

Kaltschmidt, Barbara; Uherek, Martin; Wellmann, Henning; Volk, Benedikt; Kaltschmidt, Christian

doi:10.1073/pnas.96.16.9409

Cited by 270 publications

(201 citation statements)

References 63 publications

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“…The common participation of NF-B/Rel in either cell survival (16,17,32) or cell death programs (6,8,20,21) strongly supports the relevance of this signaling pathway in regulating neuronal vulnerability. The data presented here demonstrate that the activation of distinct NF-B/Rel proteins can yield an opposite modulation of neuron survival.…”

Section: Discussionmentioning

confidence: 90%

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

Pizzi¹,

Goffi²,

Boroni³

et al. 2002

Journal of Biological Chemistry

148

122

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The transcription factors NF-B/Rel play a key role in regulating a diverse array of genes involved in cell growth, differentiation, and adaptive responses to environmental factors that are cell-and stimulus-specific (1). In the central nervous system, NF-B/Rel proteins are ubiquitously expressed in neurons and glia (2, 3) where, in addition to regulating physiological processes, they participate in pathological events associated with neurodegeneration (3, 4). Increased NF-B/Rel levels have been observed in the dying neurons of brains exposed to trauma and ischemia (5-8) as well as in brains of patients with Alzheimer's disease and Parkinson's disease (9 -11). Whether NF-B/Rel participates in a neurodegenerative program or otherwise in a neuroprotective process by increasing neuronal resistance to various noxae is still debated. Although many studies support the antiapoptotic effects of NF-B/Rel in cultured neurons (12-15), conflicting evidence has emerged from experimental models of pathological conditions affecting adult neurons. For example, some studies showed that NF-B/Rel mediates the neuroprotection elicited by the tumor necrosis factor in hippocampal cells (16,17) and promotes neuronal resistance to excitotoxicity (18) and ␤-amyloid-induced apoptosis (19). Other studies demonstrated that the activation of NF-B/Rel triggers neuronal degeneration after cerebral ischemia (6, 8) and mediates the glutamate-activated cell death program during excitotoxic insults to central neurons (4,20,21).NF-B/Rel proteins are a family of transcription factors composed of several members, including p50, p52, p65/RelA, RelB, and c-Rel, that form homo-and heterodimers capable of transmitting receptor signals to the nucleus (3,22). In resting cells, NF-B/Rel factors are retained in the cytoplasm by association with the inhibitory IB proteins. In stimulated cells, IB is phosphorylated and degradated, thus allowing the release and nuclear translocation of NF-B dimers. Recently, a more complex regulation of NF-B/Rel activation that involves modulatory phosphorylations has been emerging. The phosphorylation of NF-B/Rel components may operate to optimize their DNA binding and transcriptional activities, as well as functional interaction with coactivators (23). The diverse phenotypes of different NF-B/Rel knockout mice suggest that each NF-B/ Rel member serves unique physiological roles in vivo, presumably via the regulation of distinct sets of target genes. Thus, the opposite regulation of neuron survival by NF-B/Rel may very well depend on the activation of a distinct combination of subunits, resulting in the differential regulation of target genes and the induction of diverse genetic programs that dictate the cell fate (24 -26).In this study, we investigated the contribution of different NF-B/Rel proteins to the cell survival of brain neurons exposed to IL-1␤ 1 and glutamate, two common activators of NF-* This work was supported by grants from the Consiglio Nazionale delle Richerche (CNR 2000), the Italian Health Ministry, the Ital...

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Section: Discussionmentioning

confidence: 90%

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

Pizzi¹,

Goffi²,

Boroni³

et al. 2002

Journal of Biological Chemistry

148

122

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“…Activation of NFB in neurons is associated with neuroprotection against death-inducing stimuli such as exposure to ␤-amyloid protein, oxidative stress, and nitric oxide (14,15,18,20,47). Cytokines (ciliary neurotrophic factor, leukemia inhibitory factor, cardiotropin-1, and interleukin-6) as well as NGF through its low affinity receptor p75 promote neuronal survival through NFB activation (21,23), but to date no one has reported that members of the classic neurotrophic factor family, acting through Trk receptors, promote neuronal survival via NFB.…”

Section: Pedf-induced Expression Of Ngf Bdnf and Gdnf Mrna In Both mentioning

confidence: 99%

NFκB Activation Is Required for the Neuroprotective Effects of Pigment Epithelium-derived Factor (PEDF) on Cerebellar Granule Neurons

Yabe

Wilson

Schwartz

2001

Journal of Biological Chemistry

126

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Pigment epithelium-derived factor (PEDF) protects immature cerebellar granule cells (1-3 days in vitro)against induced apoptosis and mature cells (5؉ days in vitro) against glutamate toxicity, but its precise mechanism is still unknown. Because the transcription factor NFB blocks cell death, including neuronal apoptosis, we have investigated the ability of PEDF to exert its effects via NFB activation. PEDF induced an increased phosphorylation of IB␣, decreased levels of IB proteins, and translocation of p65 (RelA) to the nucleus followed by a time-dependent increase of NFB-DNA binding activity in both immature and mature neurons. The protective effects of PEDF against both induced apoptosis and glutamate toxicity were blocked by the addition of either the IB kinase inhibitor BAY 11-7082, which inhibits the phosphorylation of IB, or N-acetylLeu-Leu-norleucinal, which blocks proteosome degradation of IB, demonstrating that NFB is required for the neuroprotective effects of PEDF. Reverse transcription-polymerase chain reaction analysis revealed that up-regulation of the anti-apoptotic genes for Bcl-2, Bcl-x, and manganese superoxide dismutase was observed in PEDF-treated immature but not mature neurons. Up-regulation of nerve growth factor, brainderived neurotrophic factor, and glial cell-derived neurotrophic factor mRNA was long-lasting in mature neurons. These results suggest that PEDF promotes neuronal survival through activation of NFB, which in turn induces expression of anti-apoptotic and/or neurotrophic factor genes.

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“…Many studies supported the antiapoptotic effects of NF-κB (Koulich et al, 2001;Lezoualc′h et al, 1998;Maggirwar et al, 1998;Middleton et al, 2000) leading to neuronal resistance to excitotoxicity- (Yu et al, 1999) or Aβ-induced apoptosis (Kaltschmidt et al, 1999) in cultured neurons. Other studies demonstrated that the activation of NF-κB triggers neuronal degeneration after cerebral ischemia (Clemens et al, 1997;Schneider et al, 1999), mediates the glutamate-activated cell death program during excitotoxic insults to central neurons (Goffi et al, 2005;Grilli and Memo, 1999;Grilli et al, 1996;Pizzi et al, 2005a;Qin et al, 1999;Sarnico et al, 2008a) and the Aβ-mediated apoptosis (Valerio et al, 2006).…”

Section: Nf-κb In Neuron Survivalmentioning

confidence: 99%

“…However, NF-κB activation is also involved in the pathophysiology of neurological diseases associated with neurodegeneration (Clemens et al, 1997;O′Neill and Kaltschmidt, 1997;Schneider et al, 1999), where a dual role of NF-κB as regulator of apoptosis has been demonstrated and widely discussed (Grilli et al, 1996;Kaltschmidt et al, 1999;Mattson and Camandola, 2001;Pizzi and Spano, 2006;Qin et al, 1999;Yu et al, 1999). Several studies focused on the expression and regulation of NF-κB transcription factor in the nervous system as a pleiotropic regulator of target genes controlling physiological function.…”

Section: Nf-κb In Cnsmentioning

confidence: 99%

NF‐κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress

et al. 2012

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Brain cells display an amazing ability to respond to several different types of environmental stimuli and integrate this response physiologically. Some of these responses can outlive the original stimulus by days, weeks or even longer. Long-lasting changes in both physiological and pathological conditions occurring in response to external stimuli are almost always mediated by changes in gene expression. To effect these changes, cells have developed an impressive repertoire of signaling systems designed to modulate the activity of numerous transcription factors and epigenetic mechanisms affecting the chromatin structure. Since its initial characterization in the nervous system, NF-κB has shown to respond to multiple signals and elicit pleiotropic activities suggesting that it may play a pivotal role in integration of different types of information within the brain. Ample evidence demonstrates that NF-κB factors are engaged in and necessary for neuronal development and synaptic plasticity, but they also regulate brain response to environmental noxae. By focusing on the complexity of NF-κB transcriptional activity in neuronal cell death, it emerged that the composition of NF-κB active dimers finely tunes the neuronal vulnerability to brain ischemia. Even though we are only beginning to understand the contribution of distinct NF-κB family members to the regulation of gene transcription in the brain, an additional level of regulation of NF-κB activity has emerged as operated by the epigenetic mechanisms modulating histone acetylation. We will discuss NF-κB and epigenetic mechanisms as

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Inhibition of NF-κB potentiates amyloid β-mediated neuronal apoptosis

Cited by 270 publications

References 63 publications

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

Opposing Roles for NF-κB/Rel Factors p65 and c-Rel in the Modulation of Neuron Survival Elicited by Glutamate and Interleukin-1β

NFκB Activation Is Required for the Neuroprotective Effects of Pigment Epithelium-derived Factor (PEDF) on Cerebellar Granule Neurons

NF‐κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress

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