Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor

Barger, Steven W.; Mattson, Mark P.

doi:10.1016/0169-328x(96)00036-8

Cited by 184 publications

(82 citation statements)

References 47 publications

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“…A growing list of signals that can activate NF-kB in neurons includes tumor necrosis factor-a (TNF), 9 the excitatory neurotransmitter glutamate, 3 nerve growth factor (NGF), 10,11 activity-dependent neurotrophic factor (ADNF), 12 a secreted form of amyloid precursor protein 13 and cell adhesion molecules. 14 These molecules can activate NF-kB through coupling to kinase cascades including calcium/calmodulindependent kinase II, 15 Akt 16,17 and protein kinase C 18 ( Figure 2).…”

Section: The Basics Activation Of Nf-jb In Neuronsmentioning

confidence: 99%

“…Levels of p65 immunoreactivity are increased in neurons and astrocytes associated with amyloid plaques in the brains of Alzheimer's disease patients suggesting increased NF-kB activation in those cells. 74 Exposure of cultured neurons to amyloid b-peptide or a secreted form of amyloid precursor protein (sAPP) induced NF-kB activation, 13,75 suggesting a role for proteolytic products of APP in NF-kB activation in Alzheimer's disease brain cells. Levels of NF-kB activity are increased in cholinergic neurons in the basal forebrain of Alzheimer's patients.…”

Section: Chronic Neurodegenerative Disordersmentioning

confidence: 99%

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Roles for NF-κB in nerve cell survival, plasticity, and disease

2006

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Here we review evidence of roles for NF-jB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-jB activity include those engaged by neurotrophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-jB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-jB may uniquely affect cognition and behavior by regulating specific target genes. NF-jB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-jB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-jB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.

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Section: The Basics Activation Of Nf-jb In Neuronsmentioning

confidence: 99%

Section: Chronic Neurodegenerative Disordersmentioning

confidence: 99%

Roles for NF-κB in nerve cell survival, plasticity, and disease

2006

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Section: App Inhibits Uv-induced Jnk Activation and Cell Deathmentioning

confidence: 99%

“…4,8 It has been reported that sAPPa may exert its neuroprotective effect by activation of the nuclear factor-kappa B (NF-kB) signalling pathway. 4 Our microarray analysis of global changes in gene expression revealed APPmediated induction of MnSOD, which has been described as an NF-kB target gene. 28 In addition, APP activated expression of TPO1, genes regulating protein folding (mt-hsp70/mortalin) and ATP production (cytochrome-C) in mitochondria, as well as the ER chaperone calnexin.…”

Section: App Inhibits Uv-induced Jnk Activation and Cell Deathmentioning

confidence: 99%

“…1,2 The majority of APP is cleaved by the activity of a-secretase at the cell surface 1,3 leading to secretion of sAPPa, which might act as a neuroprotective cytokine and regulate gene expression. 4 In an alternative processing pathway, APP is cleaved by b-secretase at the N-terminus of the Ab domain. The generated cleavage fragment can be further processed by the activity of g-secretase to yield Ab, the major constituent of Alzheimer plaques.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

et al. 2004

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The amyloid precursor protein (APP) has been suggested to regulate gene expression. GeneChip s analysis and in vitro kinase assays revealed potent APP-dependent repression of c-Jun, its target gene SPARC and reduced basal c-Jun Nterminal kinase (JNK) activity in PC12 cells overexpressing APP. UV-induced activation of the JNK signalling pathway and subsequent apoptosis were likewise reduced by APP and this effect could be mimicked by the indirect JNK inhibitor CEP-11004. Treatment with a c-secretase inhibitor did not affect APP-mediated downmodulation of the JNK signalling pathway, suggesting that the effects might be mediated via asecretase processing of APP. In support of these data, overexpression of the Swedish mutant of APP did not inhibit SPARC expression, UV-induced JNK activation and cell death. Our data suggest an important physiological role of APP and a-secretase activity in the control of JNK/c-Jun signalling, target gene expression and cell death activation in response to cytotoxic stress.

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Activation of NF-?B protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration

et al. 1997

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The transcription factor NF-kappaB is expressed in neurons wherein it is activated in response to a variety of stress- and injury-related stimuli including exposure to cytokines such as tumor necrosis factor-alpha (TNFalpha), and excitotoxic and oxidative insults. NF-kappaB may play a role in the anti-death actions of TNFalpha in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-kappaB (TNFalpha and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO4 and amyloid beta-peptide (Abeta25-35). The neuroprotective actions of TNFalpha and ceramide were abolished in cultures cotreated with kappaB decoy DNA demonstrating a requirement for NF-kappaB activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNFalpha and ceramide in control cultures, but not in cultures cotreated with kappaB decoy DNA. FeSO4 and Abeta25-35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNFalpha and ceramide prior to exposure to FeSO4 and Abeta25-35, an effect blocked by kappaB decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and Abeta25-35; TNFalpha and C2-ceramide suppressed protein tyrosine nitration, and kappaB decoy DNA blocked the effects of TNFalpha and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO4 and Abeta, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-kappaB plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-kappaB in the pathogenesis of neuronal degeneration in Alzheimer's disease.

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Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor

Cited by 184 publications

References 47 publications

Roles for NF-κB in nerve cell survival, plasticity, and disease

Roles for NF-κB in nerve cell survival, plasticity, and disease

Regulation of gene expression by the amyloid precursor protein: inhibition of the JNK/c-Jun pathway

Activation of NF-?B protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration

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