Ketogenic Diet Regulates Uch-L1(C) To Improve Brain Energy Metabolism And Cognitive Function In AD Mice

Background:in recent years,brain energy metabolism disorder has been confirmed as a common pathophysiological change of Alzheimer’s Disease(AD),and the regulation of brain energy metabolism has also become an important target for researchers.Ketogenic diet(KD),as an alternative way of energy,can effectively regulate the energy supply of the brain.At present,KD has been widely used in the treatment of epilepsy,tumor and metabolic diseases,etc.However,the intervention effect of ketogenic diet in AD disease still needs a large number of experimental data to verify.Objective:To determine whether long-term KD intervention can improve mitochondrial function and brain energy metabolism in AD mice through Uch-L1(C)/Mfn2 signal,thus improving cognitive function.Methods:The 6-week-old APP/PS1 transgenic mice were treated with long-term isocaloric ketogenic diet for 10 months to the old stage.Wild type(WT)was used as negative control.APP/PS1 transgenic mice were divided into normal diet control group(APP con)and isocaloric ketogenic diet group(APP KD).The Y-maze and Morris water maze were used for behavioral detection.Mitochondrial morphology was observed by transmission electron microscopy.Ubiquitin carboxyl terminal hydrolase(Uch-L1)and Mitofusin-2(Mfn2)proteins and oxidative stress markers 4HNE and 8-OHdG were analyzed by western blot(WB)and immunofluorescence.ATP concentration was measured by ELISA.Apoptosis of neurons was observed by TUNEL staining.Results:The results showed that compared with the control group,the AD mice with long-term KD intervention could find the hidden platform faster in the Morris water maze behavior test(P<0.05),and obtained a larger alternating percentage in the Y-maze(P<0.05),showing better spatial recognition and working memory.KD promoted the expression of Uch-L1(C)and Mfn2 proteins by inhibiting oxidative stress in the hippocampus of mice,improved mitochondrial function,increased ATP content,and significantly reduced neuronal apoptosis.Conclusion:Our results suggest that long-term ketogenic diet intervention increases Uch-L1(C)and Mfn2 expression in the brain,and improves brain energy metabolism and cognitive function in AD mice.