Geniposide Increases Unfolded Protein Response-Mediating HRD1 Expression to Accelerate APP Degradation in Primary Cortical Neurons

Original Paper

Abstract

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.

Keywords

Alzheimer disease (AD) Amyloid precursor protein (APP) Endoplasmic reticulum stress Geniposide Hmg-CoA reductase degradation ligase (HRD1) Unfolded protein response (UPR) 

Abbreviations

AD

Alzheimer’s disease

CHX

Cyclohemide

ER

Endoplasmic reticulum

ERAD

Endoplasmic reticulum-associated degradation

HRD1

Hmg-CoA reductase degradation ligase

UPR

Unfolded protein response

Notes

Acknowledgements

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Chongqing Key Lab of Medicinal Chemistry & Molecular PharmacologyChongqing University of TechnologyChongqingChina
  2. 2.Chongqing Key Lab of Catalysis & Functional Organic MoleculesChongqing Technology and Business UniversityChongqingChina

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