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OBJECTIVES To investigate the neuroprotective effect of Gingko biloba extract 761 (EGb761) in Alzheimer's disease (AD) models both in vivo and in vitro and the underlying molecular mechanism. METHODS Cultured BV2 microglial cells were treated with Aβ1-42 to establish an in vitro AD model. The in vivo rat AD model was established by injecting Aβ1-42. Cells were pre-treated with EGb761, and the proliferation and necroptosis were examined by MTT or flow cytometry assays, respectively. In addition, the membrane potential and oxidative stress were measured. Cognitive function was evaluated by the Morris water maze, and the activation of the JNK signaling pathway was quantified by Western blotting. RESULTS Cultured BV2 cells exhibited prominent cell death after Aβ1-42 induction, and this cell death was alleviated by EGb761 pre-treatment. EGb761 was found to relieve oxidative stress and suppress the membrane potential and calcium overload. EGb761 treatment in AD model rats also improved cognitive function deficits. Both cultured microglial cells and the rat hippocampus exhibited activation of the JNK signaling pathway, and EGb761 relieved this activation in cells. CONCLUSION Our results showed that EGb761 regulated cell proliferation, suppressed necroptosis and apoptosis, relieved mitochondrial damage, and ameliorated tissue damage to improve cognitive function in AD models. All of these effects may involve the suppression of the JNK signaling pathway.