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BACKGROUND: Chronic cerebral hypoxia and ischemia have been shown to be related to occurrence of sporadic Alzheimer's disease, and β- and γ-secretase play an important role in the generation of β-amyloid protein. Early clinical symptoms in Alzheimer's disease patients include learning and memory deficits.OBJECTIVE: To measure learning and memory, as well as β- and γ-secretase activities in the hippocampus of a cerebral ischemia/hypoxia rat model with chronic cerebral hypoperfusion.DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the Department of Pathology, Capital Medical University from March to December, 2008.MATERIALS: β- and γ-secretase activity kits were purchased from R & D Systems, USA.METHODS: Male Sprague Dawley rats, aged 23 weeks, were randomly assigned to model (n = 56) and sham-surgery (n = 46) groups. Cerebral hypoperfusion rat models were established by bilateral common carotid occlusion. MAIN OUTCOME MEASURES: Morris water maze was used to test changes in escape latency and path length, and β- and γ-secretase activities were measured on days 10, 30, 90, and 180 following surgery.RESULTS: Progressive cognitive impairment resulted from 30 days of chronic cerebral hypoperfusion, which lasted for 180 days after cerebral hypoperfusion. β-secretase activity was increased at 10 days after hypoperfusion, which continued until 180 days, with a 14.25% increase compared to the sham-surgery group; γ-secretase activity was increased by 10.5%. CONCLUSION: Chronic cerebral hypoperfusion results in impaired spatial memory and upregulated β- and γ-secretase activities, which could play an important role in β-amyloid production.