Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Ab 1-42 mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Ab 1-42 mice. Furthermore, lonafarnib enhanced a7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Ab 1-42 mice, which were inhibited by a7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII-but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Ab 1-42 mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of a7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Ab 1-42 mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Ab 1-42 mice, which may be related to the improvement of BDNF content through the H-Ras-a7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition.