Traumatic Brain Injury Alters The Metabolism And Facilitates Alzheimer's Disease

Objective Alzheimer's disease(AD)is a chronic neurodegenerative disease that usually strats slowly and gets worse over time.People who suffered from traumatic brain injury(TBI)are more likely developing AD.However,the role of TBI in pathophysiology of AD remains elusive.In the study we examined the effect of traumatic brain injury(TBI)on spatial learning and memory of Alzheimer's disease(AD)mice model as well as the effect of TBI on the formation of neural plaques and the influence of amyloid precursor protein cleavaged pathway.In addition we intended to explore the effect of TBI on peripheral circulation metabolism in APP23/PS45 transgenic mice and the possible pathway invovled.Materials and Methods The mice were randomly divided into control group and TBI group at 2 months of age.The mice in TBI group were received anesthesia and single TBI treatment,and in the control group mice were just received anesthesia.Finally,the mice were sacrificed at the age of3 months.Morris water maze test weas used to explore the ability of spatial learning and memory.The expression level of APP,BACE1,CTFS,ADAM10 and PS1 protein were detected by Western blotting,the concentration of A?40 and A?42 were mesured by ELISA,the number of senile plaques was counted by immunohistochemical staining and the mRNA level of APP,BACE1 and PS1 were detected by QPCR.~1H nuclear magnetic resonance(~1H-NMR)-based metabonomics with multivariate analysis was performed to investigate the characteristic metabolites and the related metabolitc pathways in serum and urine samples of APP23/PS45mice sufferd from TBI.Results Morris water maze test showed that the escape latency was significantly different between the two groups on the third,fourth and fifth day(P<0.01).The swimming distance of the two groups was significantly different on the third day and the fifth day(P<0.01).In the space exploration memory experiment,the number of times of TBI group spent to travelled into the third quadrant,was significantly decreased(P<0.01)compared with the control group.The experimental results show that TBI aggravates the spatial learning and memory impairment of AD mice.Immunohistochemical analysis showed that TBI promoted deposition of A?,resulting in increased neuritic plaques in the brain.The protein expression of APP,BACE1 and C99,C89,A?40 and A?42 were significantly increased,while the levels of ADAM10 and PS1 protein were not changed.There was no significant difference in APP,BACE1,PS1 between the TBI group and the control group at the transcriptional level.At the same time,TBI affected the metabolic pattern of mice.The levels of alanine,choline,TMAO,glycine,histidine(P<0.05)and phenylalanine(P=0.05)in TBI group was significantly higher than the control group.Urinary metabolites showed that substances involved in glycolysis and tricarboxylic acid(TCA)circulation were disturbed and changed both in the acute and chronic phases after trauma.Conclusion TBI aggravates the pathological changes and the memory deficits in AD model mice,as well as affects the metabolic pattern of AD.Changes in metabolites are associated not only with TBI,but also with AD.TBI disrupts metabolic balance in AD mice,particularly amino acid metabolism and methylamine metabolism,which may be affected for a long time after TBI.Second,TBI may cause mitochondrial dysfunction,disrupting sugar metabolism,tricarboxylic acid cycle,and ultimately promote the pathogenesis of AD.