Mechanism For Serine Hydroxymethyltransferase 2 Regulating Mitochondrial Homeostasis And Its Biological Function In The Pathological Process Of Alzheimer’s Disease

Background Alzheimer’s disease（AD）is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment.Main clinical manifestations are cognitive dysfunctions such as learning and memory impairment,accompanied by mental dysfunction.No effective treatment can obviously improve mental disorders for AD patients.Previous studies have shown that in the brain of AD patients,changes in intracellular mitochondrial structure and dysfunction occur in the early stage,which is one of the earliest and most obvious features of brain neuron injury.Serine hydroxymethyltransferase 2（SHMT2）,located in mitochondria,is responsible for the mutual conversion of serine and glycine,the two important amino acids in the brain,facilitating the one-carbon unit metabolic cycle.Studies have shown that SHMT2 plays a vital role in maintaining mitochondrial function,but the relationship between SHMT2 and mitochondrial damage in AD is still unclear.Therefore,this study aims to research the expression pattern of SHMT2 in the early pathological state of AD,and to show the correlation between the abnormal expression of SHMT2 and AD mitochondrial dysfunction in AD,further,to clarify the potential mechanism.Objectives This study defined that the differential expression of SHMT2 for AD,and it also clarified the mechanism of SHMT2 performing in regulating mitochondrial dysfunction of AD.Method This study was conducted on animal models and cell.First,using APP/PS1double transgenic mice as an animal model,Morris water maze experiment was used to detect the spatial memory ability of 3-month-old AD mice,the prefrontal cortex and hippocampus of 3-month-old mice were selected to test SHMT2 expression level by Western blot.Secondly,complete the following studies in SH-SY5Y:1)Add Aβ_25-35（20μM）to SH-SY5Y to simulate the cell survival environment with abnormally increased extracellular Aβ,and observe whether there are abnormalities in mitochondrial functions including detecting ATP synthesis,ROS generation,glutathione levels and Mitochondrial membrane potential;2)Construct the SHMT2-stable-knockdown SH-SY5Y cell line to detect whether there are abnormalities in mitochondrial function,and mitochondrial grid morphology;3)Add Aβ_25-35（20μM）to the SHMT2-stable-knockdown SH-SY5Y cell line to detect the degree of mitochondrial dysfunction and whether it will be further aggravated;4)Construct the APPswe-stable-overexpressing SH-SY5Y cell line to detect the mitochondria whether there are any abnormalities in function,and mitochondrial grid morphology.Results 1)Compared with in the wild type（WT）mice,the increased expression of SHMT2 in the prefrontal cortex and hippocampus of 3-month-old AD mice is obvious;2)Addition of Aβ_25-35 caused mitochondrial dysfunction and upregulated expression of SHMT2 protein in SH-SY5Y;3)Mitochondrial dysfunction,intensified fragmentation of mitochondrial grid morphology can be observed in the SHMT2-stable-knockdown SH-SY5Y cell line;4)Compared with normal SH-SY5Y,the addition of Aβ_25-35 resulted in increased mitochondrial dysfunction in the SHMT2-stable-knockdown SH-SY5Y cell line;5)Mitochondrial dysfunction,increased fragmentation of mitochondrial grid morphology,and upregulation of SHMT2 protein expression can be observed in the APPswe-stable-overexpressing SH-SY5Y cell line.Conclusion In the early pathological state of AD,the expression of SHMT2 is up-regulated,and the loss of SHMT2 aggravates the abnormalities of mitochondrial morphology and function.SHMT2 may play a role in protecting neurons in the early pathological process of AD by regulating mitochondrial homeostasis.