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

Accumulation of amyloid-beta (A beta) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease, but the mechanisms underlying neurotoxicity triggered by A beta remain elusive. In the current study, we investigated the roles of cysteinyl leukotriene receptor 1 (CysLT(1)R) in A beta(1-42)-induced neurotoxicity in vitro or in vivo. In vitro exposure of mouse primary neurons to A beta(1-42) caused a gradual increases in CysLT(1)R expression. In vivo bilateral intrahippocampal injection of A beta(1-42) also elicited time-dependent increases of CysLT(1)R expression in the hippocampus and cortex of mice. The CysLT1R antagonist pranlukast not only reversed A beta(1-42)-induced upregulation of CysLT(1)R, but also suppressed A beta(1-42)-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 A beta(1-42)-injected mice. Our data indicate that CysLT(1)R is involved in A beta(1-42)-induced neurotoxicity, and that blockade of CysLT(1)R, such as application of CysLT(1)R antagonist, could be a novel and promising strategy for the treatment of Alzheimer's disease (C) 2014 Elsevier Inc. All rights reserved.