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PubMed: 21329555

Title
Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease.
Journal
The international journal of neuropsychopharmacology
Volume
15
Issue
None
Pages
77-90
Date
2012-02-01
Authors
Cai F | Chen CH | Deng Y | Liu S | Song W | Tone M | Tone Y | Tong Y | Zhou W

Evidence 0e4852ef1f
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When wild-type cells were transfected with NF-kB p65 expression plasmid, the mRNA level of BACE1 was elevated by 476.6¡21.68% (p<0.0001 relative to controls) (Fig. 5b).

p(HGNC:RELA) increases r(HGNC:BACE1) View Subject | View Object

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Evidence d4d6eac2d0
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Compared to controls, TNF-a treatment resulted in significant increase in luciferase activity in the cells transfected with the human BACE1 promoter pB1P- N1 plasmid (p<0.005) and addition of aspirin in- hibited the BACE1 transcriptional activation induced by TNF-a (p<0.005 relative to TNF-a and p>0.05 relative to controls) (Fig. 6a).

a(CHEBI:"acetylsalicylic acid") decreases r(HGNC:BACE1) View Subject | View Object

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p(HGNC:TNF) increases r(HGNC:BACE1) View Subject | View Object

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Evidence 331cf3f028
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Consistent with pB1P-N1 plasmid results, TNF-a significantly induced BACE1-NF-kB promoter activation (p<0.005) and the NSAIDs aspirin, ibuprofen and indomethacin significantly blocked the TNF-a-induced BACE1- NF-kB promoter activation (p<0.005) (Fig. 6b).

a(CHEBI:"acetylsalicylic acid") decreases r(HGNC:BACE1) View Subject | View Object

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a(CHEBI:ibuprofen) decreases r(HGNC:BACE1) View Subject | View Object

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a(PUBCHEM:3715) decreases r(HGNC:BACE1) View Subject | View Object

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p(HGNC:TNF) increases r(HGNC:BACE1) View Subject | View Object

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Evidence d159e35db9
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Our data clearly demonstrate that NSAIDs inhibit TNF-a-induced BACE1 transcription via its NF-kB cis-acting elements.

a(MESH:"Anti-Inflammatory Agents, Non-Steroidal") decreases r(HGNC:BACE1) View Subject | View Object

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act(p(FPLX:NFkappaB), ma(tscript)) increases r(HGNC:BACE1) View Subject | View Object

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p(HGNC:TNF) increases act(p(FPLX:NFkappaB), ma(tscript)) View Subject | View Object

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Evidence bf5c04a123
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Inflammation is one of major pathological changes in AD brains and NF-kB signalling plays an important role in inflammation and oxidative stress (Tong et al. 2005).

bp(GO:"NIK/NF-kappaB signaling") association path(MESH:Inflammation) View Subject | View Object

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bp(GO:"NIK/NF-kappaB signaling") association path(MESH:"Oxidative Stress") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:"Oxidative Stress") association bp(GO:"NIK/NF-kappaB signaling") View Subject | View Object

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path(MESH:Inflammation) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Brain

path(MESH:Inflammation) association bp(GO:"NIK/NF-kappaB signaling") View Subject | View Object

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Evidence 1c4202530a
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These results suggest that the 4NF-kB oligonucleotides con- taining four putative NF-kB-binding elements from the human BACE1 promoter is able to respond to NF-kB signalling to modulate a downstream gene transcription.

complex(g(HGNC:BACE1), p(FPLX:NFkappaB)) regulates r(HGNC:BACE1) View Subject | View Object

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Evidence 27089d1a4d
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Consistent with our Western blot results, a significant elevation of promoter activity was detected in cells co- expressing BACE1 reporter plasmid and NF-kB p65 (Fig. 3d).

complex(g(HGNC:BACE1), p(HGNC:RELA)) increases r(HGNC:BACE1) View Subject | View Object

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Evidence f375f79a1b
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The results showed that the protein level of p65 sig- nificantly increased to 155.40¡13.39% in AD patient samples relative to control samples (p<0.05) (Fig. 1a).

p(HGNC:RELA) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Prefrontal Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:RELA) View Subject | View Object

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Annotations
MeSH
Prefrontal Cortex

Evidence baa892598e
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Our result showed that p65 overexpression significantly increased BACE1 protein level by 232.54¡12.86% (p<0.01 relative to controls) (Fig. 5g).

p(HGNC:RELA) increases p(HGNC:BACE1) View Subject | View Object

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Evidence ff7f2c0024
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p65 expression significantly increased the amount of C99 in 20E2 cells by 152.29¡6.03% in the presence of NF-kB p65 relative to controls (p<0.001) (Fig. 5h, i).

p(HGNC:RELA) increases p(HBP:C99) View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
HEK293

Evidence ae2183a64f
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There was no significant difference in APP level between p65 transfected cells and controls (p>0.05).

p(HGNC:RELA) causesNoChange p(HGNC:APP) View Subject | View Object

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Evidence b869f38b2e
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The results showed that NF-kB p65 expression significantly increased total Ab protein concentration by 134.90¡5.74% in SAS1 cells, a stable SH-SY5Y cell stably expressing Swedish mutant APP695 (Sun et al. 2006a) (p<0.0001) (Fig. 5j).

p(HGNC:RELA) increases a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence f4c8d3121f
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BACE1 mRNA levels were also markedly increased in the cortex of AD patients (126.40¡9.01% relative to controls, p<0.05) (Fig. 1b).

p(HGNC:BACE1) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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Annotations
MeSH
Prefrontal Cortex

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:BACE1) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Prefrontal Cortex

Evidence 3daa88f992
JSON

IkBa expression plasmid was also transfected into SAS1 cells and IkBa transfection reduced Ab protein levels to 92.24¡2.68% (p<0.05).

p(HGNC:NFKBIA) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

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Annotations
Experimental Factor Ontology (EFO)
SH-SY5Y

Evidence 15a27f1beb
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TNF-a is a strong activator of NF-kB signalling pathways.

p(HGNC:TNF) increases bp(GO:"NIK/NF-kappaB signaling") View Subject | View Object

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