Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway.
Leptin attenuates BACE1 expression and amyloid-β genesis via the activation of SIRT1 signaling pathway.
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DOI：
10.1016/j.bbadis.2014.05.015
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发表时间：
2014-09
影响因子：
6.2
通讯作者：
Ghribi, Othman
中科院分区：
文献类型：
--
作者：
Marwarha, Gurdeep;Raza, Shaneabbas;Meiers, Craig;Ghribi, Othman
天冬氨酸蛋白酶β-Site AβPP裂解酶1(BACE1)催化Aβ产生的限速步骤，A GMP是阿尔茨海默病(AD)神经退行性级联反应中的一种多肽。脂肪细胞因子瘦素已被证明可减少Aβ的产生，并降低BACE1的活性和表达水平。然而，瘦素诱导的Aβ水平和BACE1表达水平的降低所涉及的信号级联尚不清楚。我们已经证明，转录因子核因子-kappaB(NF-κB)正向调控BACE1的转录。NF-κB活性受哺乳动物sirtuin SIRT1的严格调控。多项研究已经确凿地表明，瘦素激活代谢主调节因子SIRT1。在这项研究中，我们确定了SIRT1的表达和活性在多大程度上调节瘦素诱导的人神经母细胞瘤SH-SY5Y细胞BACE1表达和Aβ水平的降低。本研究还阐明和描绘了瘦素抑制BACE1表达的信号转导途径。我们的结果首次证明，瘦素通过减少p65亚基的乙酰化来减弱NF-κB的激活和转录活性，这种作用依赖于SIRT1。此外，我们的数据显示，瘦素降低了核因子-κB介导的BACE1的转录，从而减少了淀粉样蛋白-β的形成。我们的研究提供了一个有价值的见解和一个新的机制，通过它可以减少BACE1的表达和淀粉样蛋白β的产生，并可能有助于设计潜在的治疗干预措施。
The aspartyl protease β-site AβPP-cleaving enzyme 1 (BACE1) catalyzes the rate-limiting step in Aβ production, a peptide at the nexus of neurodegenerative cascades in Alzheimer Disease (AD). The adipocytokine leptin has been demonstrated to reduce Aβ production and decrease BACE1 activity and expression levels. However, the signaling cascades involved in the leptin-induced mitigation in Aβ levels and BACE1 expression levels have not been elucidated. We have demonstrated that the transcription factor nuclear factor – kappa B (NF-κB) positively regulates BACE1 transcription. NF-κB activity is tightly regulated by the mammalian sirtuin SIRT1. Multiple studies have cogently evinced that leptin activates the metabolic master regulator SIRT1. In this study, we determined the extent to which SIRT1 expression and activity regulate the leptin-induced attenuation in BACE1 expression and Aβ levels in cultured human neuroblastoma SH-SY5Y cells. This study also elucidated and delineated the signal transduction pathways involved in the leptin induced mitigation in BACE1 expression. Our results demonstrate for the first time that leptin attenuates the activation and transcriptional activity of NF-κB by reducing the acetylation of the p65 subunit in a SIRT1-dependent manner. Furthermore, our data shows that leptin reduces the NF-κB – mediated transcription of BACE1 and consequently reduces Amyloid-β genesis. Our study provides a valuable insight and a novel mechanism by which leptin reduces BACE1 expression and Amyloid-β production and may help design potential therapeutic interventions.
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影响因子：
4.8
作者：
Chen, J;Zhou, YG;Li, G
通讯作者：
Li, G
影响因子：
11.8
作者：
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Sartorelli, Vittorio
DOI：
10.1016/j.bbrc.2011.09.050
发表时间：
2011-10-14
影响因子：
3.1
作者：
Greco, Steven J.;Hamzelou, Ashkan;Johnston, Jane M.;Smith, Mark A.;Ashford, J. Wesson;Tezapsidis, Nikolaos
通讯作者：
Tezapsidis, Nikolaos
DOI：
10.3233/jad-2010-1308
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Greco SJ;Bryan KJ;Sarkar S;Zhu X;Smith MA;Ashford JW;Johnston JM;Tezapsidis N;Casadesus G
通讯作者：
Casadesus G
影响因子：
4.4
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J