Objective To explore the role of histone H3 acetylation modification of brain derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD).Methods 2 months and 8 months SAMP8 mice were used as AD model.Morris water maze was used to detect the impairment of learning and memory.Western blot was used to detect BDNF protein expression in the hippocampus,and chromatin immunoprecipitation (CHIP) was applied to study the changes of histone H3 acetylation in different BDNF promoters.Results The results of water maze test showed that the time across the target quadrant in 8 months SAMP8 mice(0.9±0.4) was significant declined compared with that of 2 months SAMP8 mice(3.7 ± ±0.9) and 8 months SAMR1 mice (3.3±0.6)(all P＜0.05).Meanwhile,compared with 2 months SAMP8 mice ((23.9±4.0) s) and 8 months SAMR1 mice ((21.5± 2.3) s),target quadrant time in the 8 months SAMP8 mice((11.7±2.8) s) was also significantly reduced(both P＜0.05).The western blot showed the expression of BDNF in the hippocampus of 8 months SAMP8 mice was significantly decreased compared with that of 2 months SAMP8 mice and 8 months SAMR1 mice(P＜0.05).Lastly,CHIP assays showed that histone H3 acetylation of BDNF exon Ⅳ and Ⅵ in the hippocampus of 8 months SAMP8 mice were remarkably decreased(P＜0.05) compared with that of 2 months SAMP8 mice and 8 months SAMR1 mice.There was no significant change of histone H3 acetylation of BDNF exon Ⅰ and Ⅲ among all groups(P＞0.05).Conclusion Histone H3 acetylation of BDNF exon Ⅳ and Ⅵ is reduced during the development of AD,which may be the mechanism underlying the impairment of learning and memory in AD.