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Regulation of human BACE1 gene expression by NF-kappa B signaling Chen, Chia-Hsiung Alan


Nuclear Factor-Kappa B (NF-κB) signaling plays an important role in gene regulation and is implicated in cell apoptosis, inflammation and oxidative stress. Binding of Inhibitor of Kappa B (IκB) to NF-κB dimers, mostly RelA (p65)/p50, causes the dimers to be sequestered in cytoplasm and remain inactive. When NF-κB-activating stimuli activate the Inhibitor of Kappa B Kinase (IKK) complex, IKK phosphorylates IκB , and NF-κB is released and translocates to the nucleus, where it interacts with NF-κB binding elements in the promoter of NF-κB target genes to modulate gene expression. One of the hallmark neuropathological features of Alzheimer's disease (AD) is the senile plaques formed by the deposition of amyloid-β peptide (Aβ) in the brain. Aβgeneration is achieved by sequential proteolytic cleavage of β-amyloid precursor protein (APP) by β-site APP cleaving enzyme (BACE1) and y-secretase. Regulation of BACE1 activity is efficient to modify Aβ production and BACE1 inhibition has become a potential target in AD treatment. BACE1 is reported to be tightly regulated at both the transcriptional and translational level. Several putative NF-κB binding elements in the human BACE1 promoter region have been identified, but the precise role of NF-κB in BACE1 gene expression remains to be defined. To investigate whether NF-KB modulates BACE1 gene expression, we first identified functional NF-κB binding elements in the BACE1 promoter region. Co-expression of NF-κB p65 and BACE1 reporter plasmid in HEK293 cells resulted in increased BACE1 promoter activity and dual-luciferase reporter assays and RT-PCR analysis revealed that N F-κB p65 regulates BACE1 gene at the transcriptional level. Neurons are speculated to be the major source of AP generation, contributing to the elevated Ap burden in AD pathogenesis, and NF- KB p65 was also demonstrated to elevate BACE1 promoter activity in neuronal-like cells. In addition, NF-κB p65 overexpression leads to elevation of C99 protein levels and increased production of Aβ40. Therefore, our results show that by modulating NF-κB signalling, BACE1 gene transcription is regulated and amyloidogenic APP processing is altered

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