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

• Aβ1–42 induced ERS and impaired insulin signaling.
• ERS inhibition alleviated the IRS-1 serine phosphorylation.
• JNK inhibition attenuated the IRS-1 serine phosphorylation.
• ERS might contribute to insulin signaling impairment via JNK activation.
• ERS/JNK/IRS-1 pathway might contribute to Aβ1–42-induced Tau hyperphosphorylation.

AimsEndoplasmic 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.MethodsChanges 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.ResultsOur 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.ConclusionsThese 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.