Journal of Biological Chemistry (Impact Factor: 4.57). 05/2012;

ABSTRACT 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.
    Current Topics in Medicinal Chemistry 01/2015; 15(999). DOI:10.2174/1568026615666150114160543 · 3.45 Impact Factor
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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.
    Neurochemistry International 01/2013; 62(3). DOI:10.1016/j.neuint.2013.01.002 · 2.65 Impact Factor
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    ABSTRACT: Periodontitis involves periodontal tissue destruction and is associated with chronic inflammation and ageing. Periodontitis has recently been recognised as a risk factor for Alzheimer's disease (AD). We showed upregulation of molecules in the AD pathway including amyloid beta (A4) precursor protein (APP), a key gene in AD, interleukin-1 beta (IL-1β), and complement component 1 (q subcomponent, A chain) (C1QA) in periodontitis compared to healthy tissues. Here, we quantitatively analysed the expression levels of APP, IL-1β, and C1QA and determined the localisation of APP in gingival tissues. Fourteen chronic periodontitis patients and 14 healthy participants were enrolled. Six samples of total RNA from two distinct sites of healthy and periodontitis-affected gingival tissues from three randomly selected patients were used for microarray analyses, and significant biological pathways in periodontitis were identified. Differential gene expression of APP, IL-1β, and C1QA, which belong to the AD pathway, were analysed with quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR) using samples from these 14 chronic periodontitis patients and 14 healthy controls. APP localisation was analysed with immunohistochemistry. APP, IL-1β, and C1QA mRNA levels were significantly upregulated in periodontitis-affected gingival tissues. APP was mainly localised in macrophages in gingival connective tissues underneath the epithelial layers. An association between AD and periodontitis was detected with microarray and computer-aided data mining analyses. qRT-PCR identified differential gene expression in periodontitis-affected gingival tissue that may be related to AD pathogenesis. Elevated APP, IL-1β, and C1QA transcripts and APP-expressing macrophages in periodontitis-affected gingival tissues were observed, suggesting a relationship between periodontitis and AD pathogenesis.
    Archives of oral biology 03/2014; 59(6):586-594. DOI:10.1016/j.archoralbio.2014.03.004 · 1.88 Impact Factor
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