Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations

Abstract

Background: NF-B regulates BACE1 but there is little data suggesting ␤APP and ␥-secretase involvement. Results: NF-B differentially regulates A␤ production at physiological and supraphysiological A␤ concentrations by modulating transactivation of ␤APP and ␥-secretase promoters, thereby controlling ␥-secretase activity. Conclusion: Under physiological conditions, NF-B regulates A␤ homeostasis while it contributes in increasing A␤ production in the pathological context. Significance: NF-B may be seen as a potential therapeutic target.

Streptozotocin-induced diabetes increases amyloid plaque deposition in AD transgenic mice through modulating AGEs/RAGE/NF-κB pathway

“…Some studies have shown that NF-κB can participate in APP processing and Aβ production, plays an important role in the pathophysiology of AD. It has been reported that NF-κB activates the transcription of βAPP, BACE1, and some of the γ -secretase members and increases protein expression and enzymatic activities, resulting in enhanced Aβ production [31][32][33]. Consistently, our results showed that STZ-induced diabetes could increase levels of AGEs, RAGE and NF-κB in APP/PS1 transgenic mice.…”

Neuronal Gene Targets of NF-κB and Their Dysregulation in Alzheimer's Disease

“…In contrast to the work of Kaltschmidt et al Chami et al (2012) confirmed NF-κB activation with Aβ but only at high (supraphysiological) levels in human embryonic kidney 293 (HEK293) cells. Bales et al (1998) reported reduced levels of constitutive p-65-mediated NF-κB activation with Aβ (25 or 50 μM) in rat cortical embryonic neurons, an effect dependent upon upregulation of IκB levels tethering cytoplasmic NF-κB.…”

“…Several studies confirm regulation of NF-κB by Aβ (Behl et al, 1994; Kaltschmidt et al, 1997, 1999; Bales et al, 1998; Valerio et al, 2006; Chami et al, 2012) that appears to be mediated by ROS (Tanaka et al, 2002). Aβ is capable of permeabilizing cell membranes (Glabe, 2006).…”

Honokiol Attenuates Oligomeric Amyloid β1-42-Induced Alzheimer’s Disease in Mice Through Attenuating Mitochondrial Apoptosis and Inhibiting the Nuclear Factor Kappa-B Signaling Pathway

“…Honokiol dose-dependently reversed these changes. Moreover, the protein expressions of two target genes of NF-κB, amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE1) [20-22], were also upregulated in the hippocampus after Aβ oligomer-stimulation and were restored after the treatment of holokiol (Fig. 4E and F).…”

“…Yang et al found that TNF-α-induced NF-κB activation did not affect APP in primary hippocampal neurons [38], while others reported that NF-κB activation upregulates promoter activity of APP in HEK293 cells [22]. Both Chami and Chen discovered that NF-κB mediated elevated BACE1 expression in HEK293 cells [22, 37], while Bourne et al reported that factor NF-κB served as a suppressor in neuronal cell lines but as an activator of BACE1 transcription in astrocytes [39]. These discrepancies may due to the difference of the cells and stimulation factors used in the studies.…”