Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations
Nuclear Factor-κB Regulates βAPP and β- and γ-Secretases Differently at Physiological and Supraphysiological Aβ Concentrations
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DOI：
10.1074/jbc.m111.333054
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发表时间：
2012-07-13
影响因子：
4.8
通讯作者：
Checler, Frederic
中科院分区：
文献类型：
--
作者：
Chami, Linda;Buggia-Prevot, Virginie;Checler, Frederic
阿尔茨海默病受影响的大脑中的解剖学病变主要包括老年斑、炎症特征和氧化应激。核因子 - κB（NF - κB）是一种应激激活的转录因子，在老年斑周围被激活。我们已经评估了在淀粉样β（Aβ）肽的生理或超生理水平下，NF - κB是否可以被差异调节。在这些实验条件下，我们描绘了所有参与Aβ产生的细胞成分中假定的NF - κB依赖性调节，即其前体βAPP（β - 淀粉样前体蛋白）以及β - 和γ - 分泌酶，这两种酶机制参与Aβ的产生。在生理条件下，NF - κB降低了HEK293细胞中βAPP、β - 分泌酶（β位点APP切割酶1，BACE1）以及γ - 分泌酶的四种蛋白质成分（Aph - 1、Pen - 2、尼卡斯特林、早老素 - 1或早老素 - 2）启动子的转录活性。这伴随着蛋白质水平和酶活性的降低，从而最终产生较少量的Aβ和AICD（APP细胞内结构域）。在稳定转染表达瑞典突变型βAPP的HEK293细胞中，引发超生理浓度的Aβ肽时，NF - κB激活βAPP、BACE1和一些γ - 分泌酶成员的转录，并增加蛋白质表达和酶活性，导致Aβ产生增加。我们使用不同的NF - κB激酶调节剂的药理学方法表明，NF - κB的经典途径和替代途径都参与了Aβ产生的控制。总体而言，我们的数据表明，在生理条件下，NF - κB对Aβ产生触发一种抑制作用，这有助于维持其体内稳态，而在病理条件下，NF - κB参与一个退化循环，其中Aβ会促进自身的产生。
Anatomical lesions in Alzheimer disease-affected brains mainly consist of senile plaques, inflammation stigmata, and oxidative stress. The nuclear factor-kappa B (NF-kappa B) is a stress-activated transcription factor that is activated around senile plaques. We have assessed whether NF-kappa B could be differentially regulated at physiological or supraphysiological levels of amyloid beta (A beta) peptides. Under these experimental conditions, we delineated the putative NF-kappa B-dependent modulation of all cellular participants in A beta production, namely its precursor beta APP (beta-amyloid precursor protein) and the beta- and gamma-secretases, the two enzymatic machines involved in A beta genesis. Under physiological conditions, NF-kappa B lowers the transcriptional activity of the promoters of beta APP, beta-secretase (beta-site APP-cleaving enzyme 1, BACE1), and of the four protein components (Aph-1, Pen-2, nicastrin, presenilin-1, or presenilin-2) of the gamma-secretase in HEK293 cells. This was accompanied by a reduction of both protein levels and enzymatic activities, thereby ultimately yielding lower amounts of A beta and AICD (APP intracellular domain). In stably transfected Swedish beta APP-expressing HEK293 cells triggering supraphysiological concentrations of A beta peptides, NF-kappa B activates the transcription of beta APP, BACE1, and some of the gamma-secretase members and increases protein expression and enzymatic activities, resulting in enhanced A beta production. Our pharmacological approach using distinct NF-kappa B kinase modulators indicates that both NF-kappa B canonical and alternative pathways are involved in the control of A beta production. Overall, our data demonstrate that under physiological conditions, NF-kappa B triggers a repressive effect on A beta production that contributes to maintaining its homeostasis, while NF-kappa B participates in a degenerative cycle where A beta would feed its own production under pathological conditions.