title: Leukotriene D4 induces amyloid-β generation via CysLT(1)R-mediated NF-κB pathways in primary neurons.
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 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.
authors: Department of Pharmacology, Laboratory for Diabetes & Brain Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors: Xiao Yun
authors: XY
authors: Wang
authors: Su Su
authors: SS
authors: Tang
authors: Mei
authors: M
authors: Hu
authors: Yan
authors: Y
authors: Long
authors: Yong Qi
authors: YQ
authors: Li
authors: Ming Xing
authors: MX
authors: Liao
authors: Hui
authors: H
authors: Ji
authors: Hao
authors: H
authors: Hong
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D017998:Leukotriene D4 / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D018077:Receptors, Leukotriene / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D017931:DNA Primers; D016328:NF-kappa B; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor