Involvement of cysteinyl leukotriene receptor 1 in Aβ1-42-induced neurotoxicity in vitro and in vivo

Neurobiol Aging. 2014 Mar;35(3):590-9. doi: 10.1016/j.neurobiolaging.2013.09.036. Epub 2013 Oct 23.


Accumulation of amyloid-β (Aβ) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease, but the mechanisms underlying neurotoxicity triggered by Aβ remain elusive. In the current study, we investigated the roles of cysteinyl leukotriene receptor 1 (CysLT1R) in Aβ1-42-induced neurotoxicity in vitro or in vivo. In vitro exposure of mouse primary neurons to Aβ1-42 caused a gradual increases in CysLT1R expression. In vivo bilateral intrahippocampal injection of Aβ1-42 also elicited time-dependent increases of CysLT1R expression in the hippocampus and cortex of mice. The CysLT1R antagonist pranlukast not only reversed Aβ1-42-induced upregulation of CysLT1R, but also suppressed Aβ1-42-triggered neurotoxicity evidenced by enhanced nuclear factor-kappa B p65, activated caspase-3, decreased B-cell lymphoma-2 and cell viability and impaired memory. Furthermore, chronic treatment with pranlukast produced similar beneficial effects on memory behavior and hippocampal long-term potentiation to memantine or donepezil in intrahippocampal Aβ1-42-injected mice. Our data indicate that CysLT1R is involved in Aβ1-42-induced neurotoxicity, and that blockade of CysLT1R, such as application of CysLT1R antagonist, could be a novel and promising strategy for the treatment of Alzheimer's disease.

Keywords: Aβ(1–42); Bcl-2; Caspase-3; Cysteinyl leukotriene receptor 1; Memory; NF-κB; Neurotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / metabolism*
  • Chromones / pharmacology
  • Chromones / therapeutic use
  • Gene Expression / drug effects*
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Leukotriene Antagonists / pharmacology
  • Leukotriene Antagonists / therapeutic use
  • Male
  • Memory
  • Mice
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • NF-kappa B / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Neurons / pathology
  • Peptide Fragments / toxicity*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Leukotriene / genetics*
  • Receptors, Leukotriene / metabolism
  • Receptors, Leukotriene / physiology*
  • Up-Regulation / drug effects


  • Amyloid beta-Peptides
  • Chromones
  • Leukotriene Antagonists
  • NF-kappa B
  • Peptide Fragments
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Leukotriene
  • amyloid beta-protein (1-42)
  • Caspase 3
  • leukotriene D4 receptor
  • pranlukast