Department of Pharmacology, Laboratory for Diabetes & Brain Diseases, China Pharmaceutical University, Nanjing 210009, China.
Neurochem Int. 2013 Feb;62(3):340-7. doi: 10.1016/j.neuint.2013.01.002. Epub 2013 Jan 11.
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 24h 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- or γ-secretase with complete abrogation by the selective CysLT(1)R antagonist pranlukast. Exposure of neurons to LTD4 for 1h 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.
虽然散发性阿尔茨海默病（AD）的发病机制尚不清楚，但神经炎症已被认为在 AD 的发病机制中起作用。为了研究神经炎症与 AD 之间的功能联系，研究了炎症脂质介质白三烯 D4（LTD4）对体外淀粉样β生成的影响。将 LTD4 应用于细胞单层，浓度高达 40 nM LTD4 会导致 Aβ 释放增加。浓度≥40 nM LTD4 会降低神经元活力。应用 20 nM LTD4 会导致 ELISA 或 Western blot 评估的 Aβ 生成显著增加，而没有明显的细胞毒性。在该浓度下，LTD4 暴露于神经元 24h 会产生最大的 Aβ 生成效果，并且半胱氨酰白三烯 1 受体（CysLT1R）的表达和β-或γ-分泌酶的活性显著增加，选择性 CysLT1R 拮抗剂 pranlukast 可完全阻断。神经元暴露于 LTD4 1h 后，通过评估核中 p65 或磷酸化 p65 的水平，NF-κB 途径被激活，CysLT1R 拮抗剂 pranlukast 或 NF-κB 抑制剂 PDTC 可防止 p65 的核易位和随后的磷酸化。PDTC 还抑制 LTD4 诱导的体外β-或γ-分泌酶活性和 Aβ 生成升高。总体而言，我们的数据首次表明，LTD4 通过激活 CysLT1R 介导的 NF-κB 信号通路增强β-或γ-分泌酶来导致 Aβ 产生。这些发现为神经炎症与 AD 之间提供了新的病理联系。
