Mechanism Of Berberine Regulating A? Production And Aggregation Based On Cdk5/p25 Signaling Pathway

Objectives:To investigate the regulation of berberine on Cdk5/p25 signaling pathway and the underlying mechanism of berberine inhibiting A? production and aggregation,providing a new scientific basis for berberine treatment of AD.Methods:40 male APP/PS1 transgenic male mice were randomly divided into 4 groups(n=10): saline group,berberine group,Cdk5 inhibitor Roscovitine group(Roscovitine group),and berberine+Cdk5 inhibitor Roscovitine Group(berberine+Roscovitine group).After adaptive feeding,Berberine group was intragastrically administered with berberine 100 mg/kg/d;the saline group was given the same amount of normal saline;the Roscovitine group was received Cdk5 inhibitor Roscovitine,10 mg/kg/d for 3 days by intraperitoneal injection,and then the same amount of saline was given intragastrically;berberine+Roscovitine group was received Cdk5 inhibitor Roscovitine,10 mg/kg/d for 3 days by intraperitoneal injection,then continued to administer berberine 100mg/kg/d.The mice in the 4 groups were continuously intragastrically administered for 4 weeks.After the end of the gavage,the water maze test was used to test the learning and memory ability of the 4 group.The expression of A?42,three secretase markers related to A? production and Cdk5/p25 signaling pathway proteins Cdk5,p25 were detected by immunohistochemistry and Western blot;immunofluorescence method to detect senile plaques formed by A? accumulation.Results:1.Compared with the saline group,the escape latency and distance of the berberine group,Roscovitine group and berberine+Roscovitine group were significantly shortened(p<0.05),and the activity time in the target quadrant was long(p <0.05),the number of stations increased(p<0.05);compared with the berberine group,there was no significant difference in the escape latency,activity time in the target and number of acrossing stations between the Roscovitine group and the berberine+Roscovitine group(p>0.05),indicating that both berberine and Cdk5 inhibitor Roscovitine can improve the learning and memory ability of mice,but there is no difference in the improvement of learning and memory ability between the two group.2.Compared with the saline group,the expression of A?42 was decreased in the berberine group,Roscovitine group and berberine+Roscovitine group(p<0.05),ADAM17 expression was increased(p<0.05).The expression of BACE1 in the cortex and hippocampus was significantly decreased(p<0.05),and the expression of presenilin1 was not significantly changed(p>0.05),indicating that both berberine and Cdk5 inhibitor Roscovitine can reduce the production of A?42 by affecting the key enzymes of A? production.Compared with the Roscovitine group and berberine+Roscovitine group,the expression of BACE1 in the hippocampus of the berberine group was significantly decreased(p<0.05),and the expression of A?42,ADAM17 and BACE1 in the hippocampus of the berberine group was not significantly changed(p>0.05),indicating that both the berberine group and the Cdk5 inhibitor Roscovitine can reduce A?42.Expression,but there was no significant difference between the two group,and there was no synergistic effect;compared with the saline group,the expression of Cdk5/p25 pathway proteins Cdk5 and p25 in the berberine group,berberine+Roscovitine group transgenic mice decreased(p< 0.05),indicating that berberine can regulate Cdk5/p25 pathway and inhibit excessive activation of Cdk5.3.Compared with the saline group,the number of senile plaques formed by A? accumulation in the berberine group,Roscovitine group and berberine+Roscovitine group was significantly decreased(p<0.05),indicating berberine and Cdk5 inhibitor Roscovitine can reduce the formation of senile plaques in the brain of mice;there is no statistical difference in the number of senile plaques between the berberine group,the Roscovitine group and the berberine + Roscovitine group.Conclusion:1.Berberine can reduce the production and aggregation of A? in the brain of APP/PS1 transgenic mice.2.The Cdk5/p25 signaling pathway is involved in the pathological process of AD.The Cdk5 inhibitor Roscovitine can reduce the production and aggregation of A? in the brain of APP/PS1 transgenic mice.3.Berberine reduces the expression of Cdk5/p25 signaling pathway-related proteins Cdk5 and p25 in the brain of APP/PS1 transgenic mice;4.Berberine could improve learning and memory ability by regulating the Cdk5/p25 signaling pathway in the brain of transgenic mice.