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

Journal of Biological Chemistry (Impact Factor: 4.57). 05/2012; 287(50). DOI: 10.1074/jbc.A115.333054


Background: NF-κB regulates BACE1 but few data concern βAPP and γ-secretase. Results: NF-κB differently regulates Aβ production at physiological and supraphysiological Aβ concentrations by modulating transactivations of βAPP and γ-secretase promoters thereby controlling γ-secretase activity. Conclusion: In physiological conditions, NF-κB regulates Aβ homeostasis while it contributes to increase Aβ production in pathological context. Significance: NF-κB could be seen as a potential therapeutic target. ABSTRACT Anatomical lesions in Alzheimer's disease-affected brains mainly consist in senile plaques, inflammation stigmata and oxidative stress. The nuclear factor-κB (

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    • "The transcriptional regulation of BACE1 gene by NF-κB is complex, but under conditions of Aβ overload the upregulation of BACE1 gene may occur through NF-κB activation [113,114]. A recent study has shown that in HEK293 cell line under physiological conditions, NF-κB actually downregulates the expression rates of genes for APP, BACE1 and several components of γ-secretase complex, but when these cells are overexpressing wild-type or mutated APP gene and having an overload of Aβ peptides, NF-κB activation positively modulates all these genes [115]. Thus, NF-κB upregulation in AD brain actually sustains a vicious cycle where increased Aβ peptide load further enhances its synthesis from the precursor protein (Fig. 2). "
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    ABSTRACT: Oxidative stress and inflammatory response are important elements of Alzheimer's disease (AD) pathogenesis, but the role of redox signaling cascade and its cross-talk with inflammatory mediators have not been elucidated in details in this disorder. The review summarizes the facts about redox-signaling cascade in the cells operating through an array of kinases, phosphatases and transcription factors and their downstream components. The biology of NF-κB and its activation by reactive oxygen species (ROS) and proinflammatory cytokines in the pathogenesis of AD have been specially highlighted citing evidence both from post-mortem studies in AD brain and experimental research in animal or cell-based models of AD. The possibility of identifying new disease-modifying drugs for AD targeting NF-κBsignaling cascade has been discussed in the end.
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    ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by aggregates of amyloid-β-peptides (Aβ). Aβ results from two sequential endoproteolytic cleavages operated on the amyloid-β precursor protein (AβPP), an integral membrane protein with a single-membrane spanning domain, a large extracellular N-terminus and a shorter, cytoplasmic C-terminus. First, β-secretase (BACE1) cleaves AβPP at the N-terminal end of the Aβ sequence to produce a secreted form of AβPP, named sAβPP, and a C-terminal membrane-bound 99-aminoacid fragment (C99). Then, γ-secretase cleaves C99 within the transmembrane domain to release the Aβ peptides of different lengths, predominantly Aβ1-40 and Aβ1-42. © 2012 IUBMB IUBMB Life, 64(12): 943-950, 2012.
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    ABSTRACT: Although the pathogenesis of sporadic Alzheimer's disease (AD) is not clearly understood, neuroinflammation has been known to play a role in the pathogenesis of AD. To investigate a functional link between the neuroinflammation and AD, the effect of leukotriene D4 (LTD4), an inflammatory lipid mediator, was studied on amyloid-β generation in vitro. Application of LTD4 to cell monolayers at concentrations up to 40 nM LTD4 caused increases in the Aβ releases. Concentrations ⩾ 40 nM LTD4 decreased neuronal viability. Application of 20 nM LTD4 caused a significant increase in Aβ generation, as assessed by ELISA or Western blotting, without significant cytotoxicity. At this concentration, exposure of neurons to LTD4 for 24 h produced maximal effect in the Aβ generation, and significant increases in the expressions of cysteinyl leukotriene 1 receptor (CysLT(1)R) and activity of β- orγ-secretase with complete abrogation by the selective CysLT(1)R antagonist pranlukast. Exposure of neurons to LTD4 for 1 h showed activation of NF-κB pathway, by assessing the levels of p65 or phospho-p65 in the nucleus, and either CysLT(1)R antagonist pranlukast or NF-κB inhibitor PDTC prevented the nuclear translocation of p65 and the consequent phosphorylation. PDTC also inhibited LTD4-induced elevations of β- or γ-secretase activity and Aβ generation in vitro. Overall, our data show for the first time that LTD4 causes Aβ production by enhancement of β- or γ-secretase resulting from activation of CysLT(1)R-mediated NF-κB signaling pathway. These findings provide a novel pathologic link between neuroinflammation and AD.
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