Effects And Mechanisms Of Fish Oil And Fenofibrate On The Pathogenesis Of APP/PS1 Alzheimer’s Disease Mice

BackgroundAlzheimer’s disease(AD)currently lacks of effective clinical interventions.Studies have shown that peroxisome proliferator-activated receptor alpha(PPARα)and omega-3polyunsaturated fatty acids are protective factors of AD,but there are also inconsistent and even contradictory reports,and the mechanism needs to be further studied.ObjectiveIn this experiment,APP/PS1 double transgenic AD mice were used as experimental subjects to study the effects and mechanisms of omega-3 polyunsaturated fatty acids(fish oil),PPARα activator(fenofibrate)and their combination on the pathogenesis of AD.Provide experimental evidence for finding effective ways to prevent AD.MethodTwelve 2-month-old wild mice with the same genetic background and 482-month-old APP / PS1 double transgenic AD mice were divided into 5 groups: Wild control group,control group,fenofibrate group,fish oil group and combined group.There are 12 animals in each group.Intragastric administration for 12 consecutive weeks:solvent for Wild control group and control group,and the rest groups were treated with fenofibrate(100 mg/kg/d),deep sea fish oil(300 mg/kg/d),fenofibrate + deep sea fish oil(100 mg/kg/d + 300 mg/kg/d).The Morris water maze method was used to test the spatial learning and memory ability of mice;immunohistochemical method was used to measure Aβ levels in the brain;Western blot method was used to determine the expression levels of cortical β-amyloid precursor(APP),Α-secretase(ADAM10),β-secretase(BACE1),and PPARα;GPO-PAP method was used to determine triglyceride and total cholesterollevels in serum;WST-1 method was used to determine cortical superoxide disproportionation Enzyme(SOD)activity.Cortical total antioxidant capacity(T-AOC)activity was measured by ABTS method.Morris water maze data were processed using repeated measures ANOVA.For the rest of the data,two independent sample t tests were used for comparison between the wild control group and the control group;one-way ANOVA was used for comparison between the control group,fenofibrate group,fish oil group,and combined group;ANOVA of factorial design was used for the interaction between fenofibrate and fish oil.P <0.05 was considered statistically significant.Results1.Spatial learning and memory ability: The decline in escape latency of the combined group is steeper than that of the control group(P = 0.047).The fish oil group stayed longer in the quadrant where the platform was located than the control group by56.81%(P = 0.039),and there was no significant difference between the other groups(P> 0.05).2.Aβ plaque levels in the brain: Aβ plaques were not seen in the Wild control group,and plaque deposition was found in the other groups.Compared with the control group,the number of plaques in the fenofibrate group,fish oil group,and combined group decreased by 49.67%,34.49%,and 46.93%(P = 0.001,P = 0.012,P = 0.004).Compared with the control group,the plaque area of the fenofibrate group and combined group was reduced by 52.34% and 35.68%(P = 0.001,P = 0.015).There is no interaction between fenofibrate and fish oil(P> 0.05).3.Expression of APP,ADAM10,BACE1 and PPARα protein in cerebral cortexAPP protein: The expression of APP in the control group was 151.69% higher than that in the Wild control group(P = 0.023),and the expression of APP in the combined group was 57.14% lower than that in the control group(P = 0.011).There is no statistically significant difference between the fenofibrate group and the fish oil group compared with the control group(P> 0.05).There is no interaction between fenofibrateand fish oil(P> 0.05).ADAM10 protein: The expression of ADAM10 in the fenofibrate group,fish oil group,and combination group all increased compared with the control group by 152.27%,211.36%,and 152.27%(P = 0.037,P = 0.008,P = 0.037).There is no interaction between fenofibrate and fish oil(P> 0.05).BACE1 protein: The expression of BACE1 in the combined group decreased by40.98% compared with the control group(P =0.045),and there was no significant difference in the other groups(P> 0.05).There is no interaction between fenofibrate and fish oil(P> 0.05).PPARα protein: PPARα expression in the control group decreased by 58.77%compared with the Wild control group(P = 0.008),and the expression levels of the fenofibrate group,fish oil group,and the combined group increased by 217.02%,146.81%,and 261.70%(P = 0.001,P = 0.007,P <0.001).There is a synergy between fenofibrate and fish oil(P = 0.047).4.Serum TG and TC levels: TG levels in the control group were 29.41% higher than those in the Wild control group(P = 0.040),and there was no significant difference in TC levels between the groups(F = 1.461,P = 0.285).There is no interaction between fenofibrate and fish oil(P> 0.05).5.Cerebral SOD and T-AOC levels: SOD activity in the control group was34.26% lower than that in the Wild control group(P =0.002);T-AOC levels in the fish oil group showed an upward trend compared with the control group(P = 0.050),and T-AOC activity in the combined group was 5.12% higher than that of the transgenic genome(P = 0.004).There is no interaction between fenofibrate and fish oil(P> 0.05).Conclusion1.There exist Aβ deposition,dyslipidemia,and reduction of PPARα expression and SOD activity in 5-month-old APP/PS1 double transgenic AD mice.2.The intervention of fish oil reduces Aβ deposition in the brain and improvescognitive function.The mechanism may be related to increasing the expression of PPARα,ADAM10,and improving the antioxidant capacity.3.The intervention of fenofibrate reduced Aβ deposition in the brain,and the mechanism may be related to activating PPARα and increasing ADAM10 expression.4.The combined intervention of fish oil and fenofibrate reduces Aβ deposition in the brain and improves cognitive function.The mechanism may be not only related to the increased expression of PPARα and ADAM10 and the increase of total antioxidant capacity,but also to the decreased expression of APP and BACE1.