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Acupuncture has been shown to ameliorate the cognitive impairment of Alzheimer's disease(AD).However,the underlying mechanism remains to be validated.This study aimed to investigate whether electroacupuncture(EA)could ameliorate cognitive deficit and modify the synapse ultrastructure in Aβ1-42-induced rat model through inhabiting GSK-3β.The AD model was established by the intracerebroventricular administrations of Aβ1-42 into the hippocampus.All rats were evaluated for their capabilities of spatial navigation and memorization by Morris water maze.Synapse ultrastructure was analyzed by electron microscopy.Western blotting tested protein levels of total GSK-3β,pSer9-GSK-3β,pTyr216-GSK-3β,APP and Aβ1-40.After 14 days of treatment,EA significantly improved behavioral deficits compared with the Aβ1–42-injected group.Electroacupuncture also significantly increased the synaptic curvatures,decreased the width of synaptic cleft,thickened the postsynaptic density,and downregulated the expression of GSK-3β,APP and Aβ1-40.pSer9-GSK-3β was markedly decreased,while pTyr216-GSK-3β was increased.And high-frequency EA has better therapeutic effects compared to low and medium-frequency EA.In conclusion,High-frequency EA exerts a protective effect against Aβ1–42-induced learning and memory deficits and synapse ultrastructure impairment via inhabiting GSK-3β activity.