IRhom1 Improves Cuprizone-induced Cognitive Impairment By Regulating Hippocampal Myelin

Multiple sclerosis?MS?is a disease of the central nervous system with myelin damage,learning and memory impairment is one of its important symptoms.In the central nervous system,myelin is a kind of phospholipid rich multilayer dense membrane structure wrapped by oligodendrocyte?OL?cell membrane is wrapped outside the axons of neurons.It has the functions of axonal insulation and improving the transmission of nerve impulses.Myelin basic protein?MBP?and myelin associated glycoprotein?MAG?are the main components of myelin,is an important structural protein.A disintegrin and metalloprotease-17?ADAM17?,a disintegrin and metalloproteinase,is essential in regulating oligodendrocyte?OL?regeneration and remyelination under demyelinating conditions.However,it is unclear how iRhom1regulates myelin formation in MS.Objective:To investigate whether there is cognitive dysfunction in demyelinating model mice and whether there is myelin damage in hippocampus of cognitive function related brain area.To study the expression of irhom1 in the brain of demyelinating mice.By establishing specific hippocampal iRhom1^highmice,we explored the function of iRhom1/ADAM17 in MS cognitive ability.Method:The demyelinating mouse model was established by cuprizone,and the specific hippocampal irhom1 high mouse was established by adeno-associated virus vector.Morris water maze?MWM?experiment was used to test spatial learning and memory ability.Detection of spontaneous activity and exploratory behavior in mice by open field test.Western blot was used to detect the expression of iRhom1,MBP,MAG,pro-ADAM,mature-ADAM17,EGFR and p-EGFR.Tissue immunofluorescence was used to evaluate the expression of MBP in hippocampus.Luxol fast blue?LFB?staining was used to analyze myelin damage in hippocampus.Real Time PCR was used to detect iRhom1,Olig2,ADAM17 m RNA levels.Result:Morris water maze,open field experiment results show that cuprizone can induce the cognitive and exploration ability of mice to reduce.The results of LFB staining and immunofluorescence showed that cuprizone could induce the damage of hippocampal myelin sheath.Western blot showed that the expression of MBP and MAG decreased,but the expression of iRhom1,mature-ADAM17 and p-EGFR increased significantly.Under the condition of demyelination,iRhom1^highin specific hippocampus could reverse the decrease of cognitive and exploration ability of mice,and prevent the demyelination induced by cuprizone.In addition,the weight of iRhom1^highmice given cuprizone was similar to that of mice fed with conventional diet.Conclusion:iRhom1 reverses Cuprizone-induced hippocampal myelin damage and cognitive dysfunction by activating the ADAM17/EGFR signaling axis,which provides new research ideas for memory loss caused by MS.