title: Leukotriene D4 induces cognitive impairment through enhancement of CysLT₁ R-mediated amyloid-β generation in mice.
abstract: Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimer's disease (AD). In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice. The results demonstrated that intracerebral infusions of LTD4 (1 ng/mouse) produced memory impairment as determined by Morris water maze test and Y-maze test in mice, and caused the accumulation of Aβ1-40 and Aβ1-42 in the hippocampus and cortex through increased activity of β- and γ-secretases accompanied with increased expression of amyloid precursor protein (APP). LTD4 also induced expression of cysteinyl leukotriene receptor 1 (CysLT(1)R) and NF-κB p65 in the hippocampus and cortex. Pretreatment with pranlukast (1.5 ng/mouse, intracerebroventricularly), a CysLT(1)R antagonist, blocked LTD4-induced amyloidogenesis, memory deficits. Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro. Moreover, LTD4-induced increases in CysLT(1)R and NF-κB p65 in the brain were also attenuated by pranlukast. These results suggest that LTD4 increases Aβ peptide burden via activation of CysLT(1)R, which further affects APP levels and activity of β- and γ-secretases via the NF-κB pathway. Our findings identify CysLT(1)R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT(1)R in neuroinflammatory diseases such as AD.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Su-Su
authors.initials: SS
authors.lastname: Tang
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.forename: Yong-Qi
authors.initials: YQ
authors.lastname: Li
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Xiang
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Jiang
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Zhang
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Liu
authors.forename: Ming-Xing
authors.initials: MX
authors.lastname: Miao
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Feng-Ying
authors.initials: FY
authors.lastname: Ye
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D057967:Infusions, Intraventricular; D017998:Leukotriene D4 / Q000008:administration & dosage* / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D017207:Rats, Sprague-Dawley; D018077:Receptors, Leukotriene / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D018836:Inflammation Mediators; D018077:Receptors, Leukotriene; D017998:Leukotriene D4; C083169:leukotriene D4 receptor