Geniposide Regulating Unfolded Protein Response Plays An Essential Role On The Degradation Of APP In Primary Cultured Cortical Neurons

Alzheimer's disease(AD)is a common neurodegenerative disease,which was characterized by senile plaques,formed by the aggregation and deposition of A? peptide,and the neurofibrillary tangle.Because the pathogenesis of this disease is very complex,there is no effective strategies for the treatment of AD,so,early prevention is particularly important for AD.An impressive number of evidence shows thatdysfunction of glucose metabolism in neurons is an important feature of neurodegenerative diseases and important reasons.And recent studies have also confirmed that hyperglycemia-induced neuronal glucose metabolism disorders does not only affect the cell second messenger function through the polyol and hexosamine pathways,but attenuate the degradation of APP,and caused the increase of A? production indirectly.In this study,we found that incubation with high concentration of glucose significantly promoted the phosphorylation of unfolded protein response(UPR)with enhancing the phosphorylation of IRE1? and eIF2?,but have no distinctively effect on the cleave of ATF6,another important signaling molecule about UPR.We also identified that geniposide couldpotentiate the phosphorylation of IRE1? in the presence of high glucose significantly.Furthermore,we observed that geniposide increased the protein level of HRD1,an ERAD-associated E3 ubiquitin-protein ligase,in the presence of high glucose in primary cultured cortical neurons.To probe the role of geniposide inducing the IRE1 ? phosphorylationand the expression of HRD1,we detected the effect ofSTF-083010,an inhibitor of IRE1? inhibitor,on the expression of HRD1,the results suggested that pre-incubation with STF-083010 remarkably attenuated the role of geniposide on the expression of HRD1.Furthermore,to determine the role of HRD1 on geniposide accelerating the degradation of APP,we knockdown the expression of HRD1 in cortical neurons with RNA interfering technique.The results demonstrated that RNAi on HRD1 prevented the effect of geniposide on the degradation of APP in high glucose-cultured primary cortical neurons.All these data suggests that,in the presence of high concentration of glucose,geniposide might enhance the phosphorylation of IRE1?,an key molecule of UPR,to induced the expression of HRD1,and then accelerate the degradation of APP.