Aim: Amyloid plaques in the extracellular parenchyma mainly consist of amyloid-β peptides (Aβ), one of the pathological hallmarks in Alzheimers disease (AD).In the present study, we examined neuroinflammation, amyloidogenesis, and memory performance following intracerebral infusions of leukotriene D4 (LTD4) in mice.Methods: We carried out behavioral tests 72 h after intracerebral infusions (1 ng/mice), and determined cysteinyl leukotriene receptor 1 (CysLT1R), Aβ, amyloid precursor protein (APP), β-or γ-secretase, and NF-κB of the brain hippocampus and cortex in mice.Results: The results demonstrated that intraeerebral infusions of LTD4 induced memory impairment determined by Morris water maze test and Y-maze test in mice, and resulted in the accumulations of Aβ40 and Aβ42 in the hippocampus and cortex of brains through increased β-and γ-secretase activities accompanied with the increased expression of APP.LTD4 also induced the expressions of CysLT1R and NF-κB p65 in the hippocampus and cortex of mouse brains.The pretreatment of pranlukast (1.5 ng/mice, intracerebrally), a CysLT1R antagonist, prevented the LTD4-induced amyloidogenesis and memory dysfunction in vivo.Pranlukast (0.6 μM) also prevented LTD4 (20 nM)-induced amyloidogenesis in the cultured neurons in vitro.Moreover, the elevated levels of brain CysLT1R and NF-κB p65 were also inhibited by pranlukast.Conclusion: Our results indicate that LTD4 signaling via the CysLT1R increased Aβ peptide burden, possibly via effects on the APP level, β-and γ-secretase activities mediated by NF-κB pathway.Our findings identify CysLT1R signaling as a novel proinflammatory and proamyloidogenic pathway, and suggest a rationale for development of therapeutics targeting the CysLT1R in neuroinflammatory diseases such as AD.