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β-Amyloid (Aβ)-induced neuronal toxicity is an early event in the pathogenesis of Alzheimer’s disease. Quetiapine (QTP) is an atypical antipsychotic drug that has neuroprotectant properties, but little is known about its direct protective effects on neurons against the Aβ-induced cell toxicity. In the present study, we investigated the neuroprotective effects of QTP on Aβ25–35-induced cell death and the possible underlying mechanisms in primary cultures of neurons. Exposure of cortical neurons to 10 μM or more Aβ25–35 caused significant viability loss in a MTT assay, and the toxic effects were not significantly prevented by the simultaneous coadministration of QTP. However, pretreated astrocyte conditioned medium (ACM) with QTP (ACMQTP) for 24 h markedly protected the neurons against the amyloid-induced cell loss. Furthermore, we revealed that QTP increased both the release of brain-derived neurotrophic factor from cultured astrocytes and the phosphorylation of extracellular signal–regulated kinase after 24 h of treatment, which might be responsible for its protective effects on neurons. Consistent with the aforementioned findings, the protective effects of ACM on neurons could potentially be abolished by the extracellular signal–regulated kinase inhibitor and tropomyosin receptor kinase B receptor blocker. In conclusion, our data demonstrated that QTP exerted its neuroprotective effects against amyloid toxicity by enhancing the brain-derived neurotrophic factor release from astrocytes.