Synaptic failure is considered as the earliest phase of Alzheimer's disease (AD) pathology.Many studies have examined the synapse density is declined, and synaptic lost is highly related to mild cognitive impairment (MCI).To find an effective phytochemical to resist or prevent the Aβ inducing synaptic dysfunction, our trial try to investigate whether the genistein (Gen) has protective effects on synapse.In this study, SH-SY5Ycells were pre-incubated with or without Gen for 2 h followed by the incubation with Aβ25-35 (25μmol/L) for another 24 h.Flow cytometry,Western blots analysis and RT-PCR analysis were used to test the synaptic related factors.The data showed that Aβ25-35 significantly down-regulated the expression of synaptophysin (SYN) and postsynaptic marker postsynaptic density-95 (PSD-95), the consistent down-regulation was also found on the expression of N-methyl-D-aspartate (NMDA) receptor subtype NR1 and NR2B in SH-SY5Y cells.On the contrary, Gen pretreatment could up-regulate the expressions of SYN/PSD-95/NR1/NR2B compared with the Aβ25-35 group.Meanwhile, the mRNA and protein expressions of (Ca2+)/calmodulin (CaM), CaMKⅡ /pCaMKⅡ and CREB/pCREB were found significantly down-regulated by Aβ25-35 in SH-SY5Y cells.However, Gen could reverse the disordered mRNA and protein expressions of CaM, CaMKⅡ /pCaMKⅡ and CREB/pCREB induced by Aβ25-35.Furthermore, Gen also maintained the intracellular calcium concentration which was reduced by Aβ25-35.Consequently, it can be speculated that Gen could protect synaptic against the damage of Aβ, and the mechanisms might be associated with the CaM/CaMKⅡ/CREB signal pathway.