Effect Of Dendrobium Nobile Lindl.alkaloids On Epigenetic Modification In Cortex Of APP/PS1 Mice

Objective:To investigate the effects of Dendrobium nobile Lindl.Alkaloids?DNLA?on improving learning and memory impairment in female APP/PS1 mice through epigenetic modification.Methods:Seven months old APP/PS1 transgenic mice were randomly divided into three groups:APP/PS1+vehicle,DNLA low-?10mg/kg?and high-dose?20mg/kg?groups.Age-matched Wild Type littermates are used as control.The DNLA groups were administered with DNLA 10,20mg/kg formulated with 1%Tween 80 double-distilled water?v/v?by gavage,and the control group and the model group were given the same volume of vehicle.Intragastric administration was given daily until the end of the 4th months.Novel object recognition test and Y maze were applied to evaluate object recognition and spatial memory processes.H&E and Nissl staining were used to detect the pathological changes of cortex.The deposition of A?_1-42 was detected by immunofluorescence.The levels of A?_1-42,DNMT1,DNMT3A,HDAC2,HDAC3 and HDAC6 was detected by Western blot and total DNA methylation in the cortex was assessed by ELISA.Results:The percentage of time exploring novel object and spontaneous alternation in Y maze test were specifically decreased in APP/PS1 mice compared with control group.Neurons in cortex of APP/PS1 mice were arranged loosely with obvious degeneration,nuclear condensation,a large number of Nissl bodies lost.Immunofluorescence showed a significant increase in the number and volume of A?_1-42 plaques in cortex.There was no significant alteration in levels of global DNA methylation and DNMT3A,HDAC2,HDAC3and HDAC6,but DNMT1 level increased in APP/PS1 mice compared with control group.The percentage of time exploring novel object and spontaneous alternation in Y maze test were specifically increased in DNLA group compared with APP/PS1 group.The regenerating nerves were more dense and orderly arranged with decreased number and density of A?_1-42 deposits in DNLA treated group.The levels of global DNA methylation,DNMT1,DNMT3A and HDAC6 did not change significantly and HDAC2 and HDAC3expression was reduced compared with APP/PS1 group.Conclusion:DNLA can improve the learning and memory impairment of female APP/PS1 mice,which may be regulated by decreasing the levels of A?_1-42,HDAC2 and HDAC3.