| First Author | Chen CH | Year | 2012 |
| Journal | Int J Neuropsychopharmacol | Volume | 15 |
| Issue | 1 | Pages | 77-90 |
| PubMed ID | 21329555 | Mgi Jnum | J:287036 |
| Mgi Id | MGI:6414694 | Doi | 10.1017/S1461145711000149 |
| Citation | Chen CH, et al. (2012) Increased NF-kappaB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol 15(1):77-90 |
| abstractText | Elevated levels of beta-site APP cleaving enzyme 1 (BACE1) were found in the brain of some sporadic Alzheimer's disease (AD) patients; however, the underlying mechanism is unknown. BACE1 cleaves beta-amyloid precursor protein (APP) to generate amyloid beta protein (Abeta), a central component of neuritic plaques in AD brains. Nuclear factor-kappa B (NF-kappaB) signalling plays an important role in gene regulation and is implicated in inflammation, oxidative stress and apoptosis. In this report we found that both BACE1 and NF-kappaB p65 levels were significantly increased in the brains of AD patients. Two functional NF-kappaB-binding elements were identified in the human BACE1 promoter region. We found that NF-kappaB p65 expression resulted in increased BACE1 promoter activity and BACE1 transcription, while disruption of NF-kappaB p65 decreased BACE1 gene expression in p65 knockout (RelA-knockout) cells. In addition, NF-kappaB p65 expression leads to up-regulated beta-secretase cleavage and Abeta production, while non-steroidal anti-inflammatory drugs (NSAIDs) inhibited BACE1 transcriptional activation induced by strong NF-kappaB activator tumour necrosis factor-alpha (TNF-alpha). Taken together, our results clearly demonstrate that NF-kappaB signalling facilitates BACE1 gene expression and APP processing, and increased BACE1 expression mediated by NF-kappaB signalling in the brain could be one of the novel molecular mechanisms underlying the development of AD in some sporadic cases. Furthermore, NSAIDs could block the inflammation-induced BACE1 transcription and Abeta production. Our study suggests that inhibition of NF-kappaB-mediated BACE1 expression may be a valuable drug target for AD therapy. |
