Insulin resistance in Alzheimer’s disease (AD) mouse intestinal macrophages is mediated by activation of JNK

Y.-L. Zhou, Y.-F. Du, H. Du, P. Shao

Department of Neurology, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China. duyifeng2013@163.com

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• Neurology

OBJECTIVE: Alzheimer’s disease (AD) has been considered as a metabolic disorder disease, which closely related to insulin signaling impairment. Therefore, identifying the potential mechanism of insulin resistance is important for AD treatment.

MATERIALS AND METHODS: An APP/PS1 double transgenic AD mouse model was introduced to study insulin resistance in gut. The expressions of AD markers and key elements of insulin signaling were detected in ileum and intestinal macrophages of AD mice by immunohistochemistry. Furthermore, mouse intestinal macrophage cell line RAW264.7 was treated by Aβ25-35 or Aβ25-35 + insulin to explore the mechanism of insulin resistance in vitro. The expression of IR-β and the activation of cell signaling related proteins (Insulin receptor substrate 1 (IRS1), protein kinase B (AKT) and c-Jun N-terminal kinase (JNK)) in Aβ25-35-stimulated macrophages were performed via Western blotting.

RESULTS: The expressions of IRS1, Aβ and Tuj in AD mice ileum were significantly different from WT mice (p<0.05). Also, there were significant discrepancies in the expressions of β2AR and eNOS in intestinal macrophages of two groups (p<0.05). After exposure to Aβ25-35, cell proliferation rate (p<0.01) of macrophage and the levels of TNF-α (p<0.01) and Il-6 (p<0.01) was significant elevated and treatment with insulin could reverse these changes (p<0.05). The amount of IR-β and the p-AKT/AKT ratio significantly decreased in Aβ25-35-treated macrophages (p<0.01), while the ratios of p-IRS1/IRS1 and p-JNK/JNK significantly enlarged (p<0.01). Furthermore, all the changes caused by Aβ25-35 treatment were attenuated by insulin addition.

CONCLUSIONS: Activation of JNK pathway played an important role in insulin resistance of AD mice, suggesting that inhibition of JNK pathway might be a new strategy toward resolving insulin resistance related diseases, such as AD.

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