Objective To investigate the mechanism of the soluble Aβ oligomersinduced alteration of synaptic proteins. Methods This study applied immunocytochemistry technique to investigate the changes of the expression of postsynaptic density-95(PSD-95) in primary hippocampal neurons, which was exposed to Aβ25-35 after NMDAR antagonist or agonist treatment. Results The results showed that Aβ25-35 downregulated PSD-95 protein in a dose and timedependent manner. Treatment of cells with MK801 (a general NMDA receptor antagonist) prevented Aβ-induced PSD-95 degradation. Moreover, when extrasynaptic NMDA receptors were blocked by ifenprodil (a NR2B subunit specific antagonist), the Aβ-induced downregulation of PSD-95 was significantly attenuated. Whereas, when synaptic NMDA receptors were blocked by bicuculline (a GABA receptor antagonist) in combination with MK801, the PSD-95 degradation did not change significantly.Conclusion The results suggest