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Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid β oligomer-treated PC12 cells and primary neurons.
Gene 2016; 587(2):183-93GENE

Abstract

AIMS

Endoplasmic reticulum stress (ERS) and insulin signaling impairment are commonly observed in Alzheimer's disease (AD), but the association between these two factors in AD has not been carefully studied. In peripheral insulin signaling impairment, ERS interferes with insulin signaling through c-Jun. N-terminal kinase (JNK)-dependent insulin receptor substance-1 (IRS-1) serine phosphorylation. We conducted this study to determine whether a similar mechanism contributes to insulin signaling impairment in AD pathogenesis.

METHODS

Changes in the levels of ERS markers, JNK activation, the insulin signaling status and Tau hyperphosphorylation were examined in amyloid β1-42 (Aβ1-42) oligomer-treated PC12 cells and primary neurons by western blotting and real-time fluorescence quantitative PCR. Inhibitors of ERS and JNK were utilized to confirm their association.

RESULTS

Our results demonstrated that Aβ1-42 oligomers significantly induced ERS and JNK activation. In addition, in response to Aβ1-42 oligomers, IRS-1 phosphorylation at serines 307, 318 and 612 was increased. Further, an increase in Tau hyperphosphorylation at threonine 181 was observed following Aβ1-42 oligomer treatment. Moreover, inhibition of ERS or JNK could partially reverse the changes induced by the Aβ1-42 oligomers.

CONCLUSIONS

These findings suggest that ERS may contribute to insulin signaling impairment in AD through JNK-dependent IRS-1 serine phosphorylation. The ERS/JNK/IRS-1 pathway may be involved in Aβ1-42 oligomer-induced Tau hyperphosphorylation in AD.

Authors+Show Affiliations

Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China.Department of Neurology, Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, PR China. Electronic address: neurology2014j@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27185631

Citation

Zhang, Xiao, et al. "Endoplasmic Reticulum Stress Mediates JNK-dependent IRS-1 Serine Phosphorylation and Results in Tau Hyperphosphorylation in Amyloid Β Oligomer-treated PC12 Cells and Primary Neurons." Gene, vol. 587, no. 2, 2016, pp. 183-93.
Zhang X, Tang S, Zhang Q, et al. Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid β oligomer-treated PC12 cells and primary neurons. Gene. 2016;587(2):183-93.
Zhang, X., Tang, S., Zhang, Q., Shao, W., Han, X., Wang, Y., & Du, Y. (2016). Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid β oligomer-treated PC12 cells and primary neurons. Gene, 587(2), pp. 183-93. doi:10.1016/j.gene.2016.05.018.
Zhang X, et al. Endoplasmic Reticulum Stress Mediates JNK-dependent IRS-1 Serine Phosphorylation and Results in Tau Hyperphosphorylation in Amyloid Β Oligomer-treated PC12 Cells and Primary Neurons. Gene. 2016 Aug 10;587(2):183-93. PubMed PMID: 27185631.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endoplasmic reticulum stress mediates JNK-dependent IRS-1 serine phosphorylation and results in Tau hyperphosphorylation in amyloid β oligomer-treated PC12 cells and primary neurons. AU - Zhang,Xiao, AU - Tang,Shi, AU - Zhang,Qinghua, AU - Shao,Wen, AU - Han,Xiaojuan, AU - Wang,Yongxiang, AU - Du,Yifeng, Y1 - 2016/05/13/ PY - 2016/01/24/received PY - 2016/04/30/revised PY - 2016/05/12/accepted PY - 2016/5/18/entrez PY - 2016/5/18/pubmed PY - 2017/1/14/medline KW - Alzheimer's disease KW - Endoplasmic reticulum stress KW - Insulin signaling impairment KW - Tau hyperphosphorylation SP - 183 EP - 93 JF - Gene JO - Gene VL - 587 IS - 2 N2 - AIMS: Endoplasmic reticulum stress (ERS) and insulin signaling impairment are commonly observed in Alzheimer's disease (AD), but the association between these two factors in AD has not been carefully studied. In peripheral insulin signaling impairment, ERS interferes with insulin signaling through c-Jun. N-terminal kinase (JNK)-dependent insulin receptor substance-1 (IRS-1) serine phosphorylation. We conducted this study to determine whether a similar mechanism contributes to insulin signaling impairment in AD pathogenesis. METHODS: Changes in the levels of ERS markers, JNK activation, the insulin signaling status and Tau hyperphosphorylation were examined in amyloid β1-42 (Aβ1-42) oligomer-treated PC12 cells and primary neurons by western blotting and real-time fluorescence quantitative PCR. Inhibitors of ERS and JNK were utilized to confirm their association. RESULTS: Our results demonstrated that Aβ1-42 oligomers significantly induced ERS and JNK activation. In addition, in response to Aβ1-42 oligomers, IRS-1 phosphorylation at serines 307, 318 and 612 was increased. Further, an increase in Tau hyperphosphorylation at threonine 181 was observed following Aβ1-42 oligomer treatment. Moreover, inhibition of ERS or JNK could partially reverse the changes induced by the Aβ1-42 oligomers. CONCLUSIONS: These findings suggest that ERS may contribute to insulin signaling impairment in AD through JNK-dependent IRS-1 serine phosphorylation. The ERS/JNK/IRS-1 pathway may be involved in Aβ1-42 oligomer-induced Tau hyperphosphorylation in AD. SN - 1879-0038 UR - https://www.unboundmedicine.com/medline/citation/27185631/Endoplasmic_reticulum_stress_mediates_JNK_dependent_IRS_1_serine_phosphorylation_and_results_in_Tau_hyperphosphorylation_in_amyloid_β_oligomer_treated_PC12_cells_and_primary_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-1119(16)30384-5 DB - PRIME DP - Unbound Medicine ER -