| Background: Diabetic cognitive dysfunction is one of the most common chronic complications of diabetes.It has been demonstrated that impaired clearance of cerebral amyloid β-protein(Aβ)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 mTORC1/SREBP-1/LRP1 signaling pathway in the brain Aβ efflux clearance impairment caused by diabetes.Methods: We constructed a model of the blood-brain barrier by culturing human brain microvascular endothelial cells in vitro.The effects of diabetes on the Aβefflux clearance across the blood-brain barrier were simulated by exposure of HBMECs to different concentrations of glucose.After high glucose treatment(25 mM,50 mM),we used qRT-PCR,Western blot,Immunofluorescence staining and other methods to detect the expression of related proteins involved in the regulation of Aβefflux transport.The effects of SREBP-1 and mTORC1 on Aβ clearance were examined by blocking the SREBP-1 and mTORC1 signals using the inhibitors betulin and rapamycin.Results: High glucose destroyed the efflux clearance of Aβ across the blood-brain barrier.High glucose decreased the expression of LRP1 of HBMECs and increased the expression of SREBP-1.Inhibition of SREBP-1 activity could effectively block the down-regulation of LRP1 expression caused by high glucose and improve the efflux clearance of Aβ across the blood-brain barrier.High glucose promoted the phosphorylation level of mTOR,S6K1 and 4EBP1,and induced theactivation of mTORC1.Inhibiting mTORC1 signaling protected against the Aβ efflux impairment induced by high glucose.Conclusions: High glucose induced the expression of SREBP-1 protein by activating mTORC1,which led to down-regulation of LRP1 expression in brain microvascular endothelial cells,resulting in Aβ efflux impairment across the blood-brain barrier and cognitive dysfunction in diabetes. |
PDF Full Text Request