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

Abstract

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.