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

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).

Evidence d4d6eac2d0

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).

Evidence 331cf3f028

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).

Evidence d159e35db9

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

Evidence bf5c04a123

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).

Evidence 1c4202530a

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.

Evidence 27089d1a4d

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).

Evidence f375f79a1b

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).

Evidence baa892598e

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

Evidence ff7f2c0024

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).

Evidence ae2183a64f

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

Evidence b869f38b2e

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).

Evidence f4c8d3121f

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).

Evidence 3daa88f992

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

Evidence 15a27f1beb

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

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