| Objective : Atherosclerosis is a chronic and progressive arterial disease characterized by lipid deposition in the vascular intima,also a risk factor and pathological basis for cardiovascular and cerebrovascular diseases.The relationship between atherosclerosis and cognitive impairment has attracted growing attention recently.A series of pathological changes of brain structure and function,such as decreased cerebral blood flow,increased microvascular injury,increased blood-brain barrier permeability,intensified inflammatory response and oxidative stress,white matter lesions,and abnormal brain metabolism may be caused by atherosclerosis,thus inducing impairment of synaptic plasticity and cognitive function.It is speculated that abnormal brain metabolism is the root cause and core mechanism of decreased synaptic plasticity and impaired cognitive function caused by atherosclerosis,while signal pathways that are closely related to energy metabolism such as AMPK,SIRT1,mTOR may play a key regulatory role in metabolic disorders and cognitive impairment caused by atherosclerosis.Aerobic exercise,an effective means to interfere with substance metabolism and energy balance,can also participate in the regulation of brain metabolism.Therefore,this study has constructed a peripheral atherosclerosis rat model by high-fat diet associated with an intraperitoneal injection of vitamin D3 to explore the effect of atherosclerosis on the expression of synaptic plasticity associated proteins and cognition function,to find out the relation between decreased synaptic plasticity associated proteins and disrupted hippocampal metabolism,and reveal the intervention effect of aerobic exercise.Methods:Forty-two healthy male SD rats were randomly distributed into the control group(C,N=10)and a high-fat diet group(HFD,N= 32).Rats in the HFD group were raised by a high-fat diet combined with vitamin D3 intraperitoneal injection for 10 weeks.In the last of the tenth week,blood glucose and lipid profile for all animals were obtained,and the rats with hyperlipidemia and hypercholesterolemia were taken as being atherosclerotic(M,n=18).To make sure arterial disease has occurred,2 rats from the atherosclerotic model group and one from the control group were selected randomly to isolate the aorta for immuno-histochemical staining.The rest rats in the M group were randomized to the atherosclerosis group(AS,n=8)and aerobic training atherosclerosis group(TAS,n=8).The TAS rats were adapted to the treadmill for 3 days,the running speed was15 m/min for 15 min.After that,the TAS group were subjected to 4 weeks of aerobic exercise(5 days/week),while the AS group were handled equally except for aerobic exercise intervention.The Y maze was used to evaluate initial memory by detecting spontaneous alternation as well as recognition memory the day after the last training.Before decapitation,all animals were fasting overnight.The rats were fixed and the exposed tail was wiped with alcohol,then the blood was collected with a blood collection needle in the tail vein for blood glucose and lipid profile.Brain tissue from all rats was collected to isolate all hippocampal tissues for further experiment after anesthesia the next day.The changes of metabolites in the hippocampus of rats were detected by GC-MS.The expression of major substrate transporters including FATP-1/GLUT-1/MCT1/MCT2,crucial metabolic enzymes such as AR/G6PD/SCOT/FASN/P-ACC/ACC/SDHA/DHCR24,synaptic plasticity associated proteins like SY38/Homer/PSD95/NMDAR/GABAR,and signal pathways closely related to energy metabolisms such as AMPK,SIRT1,mTOR-raptor/rictor-P70S6K/4EBP,and NF-?B/NLRP3/IL-1? were detected by western blot.Results:(1)The blood-lipid disorder was found in rats with atherosclerosis,which was presented as blood TC,TG,and LDL in rats of AS group was all higher than those in rats of C group(p < 0.01),but were at the similar level when compared with those in rats of TAS group before aerobic exercise intervention.After 4 weeks of aerobic exercise,the level of TC and LDL in rats of AS group were still higher than those in rats of C group(p < 0.01),while the level of LDL in the TAS group was lower than that in rats of AS group(p < 0.01).(2)Abnormal metabolism was found in the hippocampus of rats with atherosclerosis: compared to the control group,metabolites including xylulose 5-phosphate,threonine,succinate,and nonanoic acid were markedly elevated,whereas methyl arachidonic acid and methyl stearate decreased in the AS group.(3)Disrupted hippocampal metabolism was improved by exercise in rats with atherosclerosis: After 4 weeks' aerobic exercise,the levels of succinic acid,branched chain amino acids,nonanoic acid,desmosterol,and aldose reductase decreased,whereas methyl arachidonic acid,methyl stearate,and glyceraldehyde-3-phosphate elevated in the hippocampus of the TAS group in comparison with the AS group.(4)Compared to the control group,elevated FATP-1/MCT1 and decreased GLUT-1/ MCT2 expression were found in the AS group.What's more,the expression GLUT1 was upregulated in the TAS group compared with the AS group.(5)The number of novel arm entries and the amount of time spent in novel arm were reduced in the two-trial recognition memory test in the AS group,while the above indicators showed an upward trend in TAS group.(6)Compared to the control group,the expression of synaptic plasticity associated proteins Homer1 a,SY38,and GABAR was downregulated in the AS group,while Homer1 a and SY38 expression showed an increasing tendency in TAS group.(7)AR and G6 PD were upregulated,meanwhile FASN and ACC were downregulated in the hippocampus of atherosclerotic rats when compared to control rats.After 4 weeks of aerobic exercise,AR was downregulated in the hippocampus of atherosclerotic rats.(8)Compared to the control group,p-AMPK/AMPK was upregulated in the hippocampus of atherosclerotic rats,which showed a decreasing tendency in TAS group.(9)Compared to the control group,SIRT1 was downregulated in the hippocampus of atherosclerotic rats.After 4 weeks of aerobic exercise,SIRT1 was upregulated in TAS group.(10)Compared to the control group,the expression of RAGE was elevated and NF-?B-NLRP3-IL-1? pathway was activated in the hippocampus of atherosclerotic rats.Compared to the AS group,IL-1? protein was downregulated in TAS group.(11)Compared to the control group,the expression of mTOR,Raptor,Rictor,and 4EBP were decreased.After 4 weeks of aerobic exercise,the expression of 4EBP showed an upward trend in TAS group.Conclusions:Abnormal metabolism was detected in the hippocampus of rats with atherosclerosis,which was showed as reduced glycolysis,disruption of the tricarboxylic acid cycle,activation of the pentose phosphate pathway,impairment of fatty acid oxidation,and disruption of cholesterol synthesis and amino acid metabolism,accompanied by the activation of AMPK signaling and NF-?B/NLRP3/IL-1? signaling pathway in the hippocampus,leading to excessive inflammatory response,thereby inhibiting the mTOR signaling pathway and synaptic plasticity associated proteins.Aerobic exercise can effectively improve blood-lipid disorder and hippocampal metabolism caused by atherosclerosis,which was proved by increased glycolysis and tricarboxylic acid cycle,inhibition of polyol pathway,reduction of fatty acid ? oxidation,improvement of cholesterol homeostasis,and inhibition of hippocampal inflammatory response. |
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