The Roles And Mechanism Of LRP1 In Cognitive Impairment In Diabetes Mellitus

Background: The incidence of cognitive dysfunction in diabetes is increasing year by year,placing a heavy burden on families and society.It has been shown that impaired cerebral Aβ clearance is a central event in the initiation and progression of Aβ deposition and cognitive impairment in diabetics.Objective: To investigate the role and mechanism of LRP1 in Aβ clearance impairment and damaged cognitive function caused by diabetes.Methods: SPF male C57BL/6 mice were bred,and STZ(60mg/kg.d)was intraperitoneally injected for 5 days to establish a type 1 diabetes model.New object recognition experiments and fear tests were used to assess the cognitive function of mice in each group.Western Blot,q RT-PCR,ELISA and immunofluorescence staining were used to detect the expression levels of Aβ and proteins related to Aβclearance in the brains of mice.HBMECs were cultured in vitro to simulate the blood-brain barrier,and the clearance rate of Aβ and the expression levels of LRP1 were measured under different glucose concentration culture conditions.HBMECs were transfected with lentivirus to overexpress or knock down the LRP1 gene,and then the changes in Aβ clearance were detected again.AAV9-SP-A-LRP1 sh RNA adeno-associated virus vector was constructed.On the 4th day after successful modeling of T1 DM mice,the adeno-associated virus particles were injected into the tail vein of mice to selectively knock down the LRP1 gene in mice cerebral vascular endothelial cells.Then the cognitive function and the expression levels of Aβ and Aβclearance related proteins in the brain of normal,TIMD and LRP1 knockdown mice were detected.Results: Compared with the control group,diabetic mice had impaired cognitive function,increased deposition of Aβ in the brain,and decreased expression of LRP1 in brain microvessels.In vitro experiments,high glucose can down-regulate the expression of LRP1 in HBMECs and damage the efflux clearance of Aβ across the blood-brain barrier.The reduction of clearance rate of Aβ induced by high glucose was reversed by LRP1 overexpression,while the reduction of clearance rate of Aβinduced by high glucose was further decreased when LRP1 was knocked down.Cerebrovascular endothelial cell-specific LRP1 knockout mice with type 1 diabetes mellitus had further reduced cognitive function and further increased Aβ deposition in the brain compared with diabetic mice.Conclusion: Hyperglycemia can cause impaired Aβ efflux in the brain,via down-regulating the expression of LRP1 in brain microvessels,and then cause cognitive impairment.