Objective:Long-term exercise plays protective role in hypertension and Alzheimers disease,however,no exact evidence and mechanisms on the role of exercise in hypertension induced Alzheimer pathology exists so far.The aim of this study was to investigate the mechanism involved in Aβ deposition and the effects of physical exercise on cognitive function in stroke-prone spontaneously hypertensive rats(SHRSP).Methods:A total of 20 three month oid SHRSP were randomly divided into physical exercise hypertensive group(PE,n=10),which was given running wheel exercise for 4 months with moderate intensity,and sedentary hypertensive group(SED,n=10).A total of 10 Wistar rats were set as normotensive group(NC,n=10),which were fed in standard cages without any special training exercise.The blood pressure(BP)was monitored every week.Morris maze test was performed to evaluate cognitive function.The rats were sacrificed after Morris water maze test to detect the specific marker eNOS,β-site APP-cleaving enzyme 1(BACE1)by Immunofluorescence staining.We detected protein levels of insulin-like growth factor-1(IGF-1),phosphatidylinositol 3-kinase(P<0.05)and p-Akt(ser473)by western blotting in brain cortex and hippocampus of SHR.The total Aβx-42 was quantified by ELISA,using the colorimetric Beta Mark Aβx-42 ELISA kit in brain cortex and hippocampus of SHRSP.All data were presented as mean ± SD.Results of BP and escape latency were compared using repeated measures ANOVA.Results of time spent in the target quadrant,number of platform crossing,western blotting and ELISA were analyzed using one-way ANOVA,followed by Bonferroni test among three groups or two independent samples t-test for 2-group comparisons.Results:BP in PE is much lower than that in SED(P<0.05),but higher than that in NC(p<0.05).There was no significant difference between 3-month old WKY and 3-month old SHRSP in Morris water maze test.Water maze performance in PE is better than that in SED 7-month old SHR(P<0.05).The hypertensive challenge had an effect on eNOS down-regulation(P<0.05),amyloid precursor protein(APP)(P<0.05)and β-secretase(BACE1)(P<0.05)up-regulation,Aβ deposition(P<0.05)in cortex and hippocampus,leading to cognitive impairment.16-week exercise promoted eNOS expression and meliorated Alzheimer pathology,as showed by improving cognitive impairment(P<0.05),decreasing APP(P<0.05),BACE1(P<0.05),Aβ(P<0.05 deposition in 7-month SHRSP).We further found protein levels of IGF-1(P<0.05),PI3K(P<0.05)and p-Akt(ser473)(P<0.05)decreased,and long-term exercise enhanced expression of IGF-1(P<0.05)and PI3K(P<0.05)/p-Akt(ser473)(P<0.05)in brain cortex and hippocampus of SHRSP.Conclusions:eNOS promoted by long-term exercise in brain was crucial to prevent hypertension-induced Alzheimer pathology and cognitive impairment,suggesting that long-term exercise starting at young age may delay the onset of vascular-related Alzheimer.