Geniposide Increases Unfolded Protein Response-Mediating HRD1 Expression to Accelerate APP Degradation in Primary Cortical Neurons
Altered proteostasis induced by amyloid peptide aggregation and hyperphosphorylation of tau protein, is a prominent feature of Alzheimer’s disease, which highlights the occurrence of endoplasmic reticulum stress and triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis. In this study, we investigated the role of geniposide in the activation of UPR induced by high glucose in primary cortical neurons. We found that high glucose induced a significant activation of UPR, and geniposide enhanced the effect of high glucose on the phosphorylation of IRE1α, the most conserved UPR signaling branch. We observed that geniposide induced the expression of HRD1, an ubiquitin-ligase E3 in a time dependent manner, and amplified the expression of HRD1 induced by high glucose in primary cortical neurons. Suppression of IRE1α activity with STF-083010, an inhibitor of IRE1 phosphorylation, prevented the roles of geniposide on the expression of HRD1 and APP degradation in high glucose-treated cortical neurons. In addition, the results from RNA interfere on HRD1 revealed that HRD1 was involved in geniposide regulating APP degradation in cortical neurons. These data suggest that geniposide might be benefit to re-establish proteostasis by enhancing the UPR to decrease the load of APP in neurons challenged by high glucose.
KeywordsAlzheimer disease (AD) Amyloid precursor protein (APP) Endoplasmic reticulum stress Geniposide Hmg-CoA reductase degradation ligase (HRD1) Unfolded protein response (UPR)
Endoplasmic reticulum-associated degradation
Hmg-CoA reductase degradation ligase
Unfolded protein response
This work was supported by grants from Chongqing Science and Technology Committee (CSTC, 2015jcyjbx0064), Chongqing Science Found for Distinguished Young Scholars (2014jcyjjq10003), the Innovation of Science and Technology Leading Talent in Chongqing (2014kjcxljrc0018), the Innovative Research Team Development Program at the University of Chongqing (CXTDX201601031), and Chongqing University of Technology (2015XH23, 2015ZD26).
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