Journal of Biological Chemistry (Impact Factor: 4.6). 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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    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; 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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    ABSTRACT: We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixture of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-nilvadipine is the active enantiomer responsible for the inhibition of LCC whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aβ production and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (Tg Tau P301S) with (-)-nilvadipine reduces tau hyperphosphorylation at several AD pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compound inhibits the spleen tyrosine kinase (syk). We further validated syk as a target regulating Aβ by showing that pharmacological inhibition of syk or downregulation of syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and Tg Tau P301S mice with a selective syk inhibitor respectively decreased brain Aβ accumulation and tau hyperphosphorylation at multiple AD relevant epitopes. We show that syk inhibition induces an increased phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase-3β, a primary tau kinase involved in tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of tau phosphorylation at GSK3β dependent epitopes following syk inhibition. Altogether our data highlight syk as a promising target for preventing both Aβ accumulation and tau hyperphosphorylation in AD.
    Journal of Biological Chemistry 10/2014; 289(49). DOI:10.1074/jbc.M114.608091 · 4.60 Impact Factor