Objective:To investigate change in spatial learning and memory function of rats following chronic hypoperfusion for 3 months,and the neuroprotective effect of long-term treatment with 17β-estrogen (E2),which aims to outline the molecular mechanisms of progressive lesions in vascular dementia. Methods:Chronic hypoperfusion in adult male Sprague–Dawley rats was induced by permanent bilateral common carotid artery occlusion (BCCAO) and the rats were randomly assigned into three groups:the sham group,the placebo (Pla) and the E2 group. Morris water maze was performed to observe spatial learning and memory function of rats. Immunofluorescence staining and Western blot analysis were performed to detect protein expressions of synaptic markers in hippocampal CA1 region. Results:(1) Morris water maze analysis revealed no statistical differencal in latency time to find sub-water platform between the sham and the Pla groups,but the Pla group significantly decreased probe time in the quadrant where the platform was previously located compared to sham animals. (2) Compared with the sham group,the number of NeuN-positive cells and the protein level of microtubule-associated protein (MAP) 2 of the Pla group had no significant changes,however,the levels of myelin basic protein (MBP)-2 were significantly decreased. (3) In the Pla group,post-synaptic density protein 95 (PSD95) and synaptophysin were significantly decreased compared to the sham group in hippocampal CA1 region. (4) Long-term treatment with E2 reversed these changes induced by BCCAO. Conclusion:BCCAO for 3 mon could lead to decreased spatial learning and memory function of rats. Long-term treatment of E2 may block progressive lesions in vascular dementia by up-regulating MBP2,PSD95 and synaptophysin in hippocampal CA1 region.