Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China
Department of Neurology, the First People's Hospital of Chang Zhou, Jiang Su 213003, China.
Biosci Rep. 2018 Jul 12;38(4). doi: 10.1042/BSR20171284. Print 2018 Aug 31.
This study aimed to validate whether glucagon-like peptide-1 receptor (GLP-1R) / cyclic adenosine monophosphate (cAMP) / protein kinase (PKA) / insulin-degrading enzyme (IDE) signaling pathway was associated with neuronal apoptosis. We developed an animal model presenting both Alzheimer's disease (AD) and type 2 diabetes (T2D), by crossing APP/PS1 mice (AD model) with streptozotocin (STZ)-treated mice (a T2D model). Neuronal apoptosis was detected by TUNEL staining and the expression levels of apoptosis-related proteins were examined by Western blotting. The viability of PC12 cells was analyzed by MTT assay and apoptosis of PC12 cells was detected by flow cytometry. The mRNA expression level was detected by qRT-PCR. T2D contributes to AD progress by prompting neuronal apoptosis and increasing expression of pro-apoptotic protein. β-Amyloid peptide1-42 (Aβ1-42) was shown to exert effects on inhibiting cell viability and prompting cell apoptosis of PC12 cells. However, GLP-1R agonist geniposide (Gen) significantly reversed them, exerting a protective role on PC12 cells. And IDE antagonist bacitracin (Bac) markedly reversed the protective effects of Gen on Aβ1-42-treated PC12 cells. Besides, Gen significantly reversed the effects of Aβ1-42 treatment on IDE expression, and the inhibitor of cAMP/PKA signaling pathway markedly reversed the effects of Gen on IDE expression level in Aβ1-42-treated PC12 cells. In conclusion, GLP-1R regulates cell growth, at least partially, through regulating cAMP/PKA/IDE signaling pathway in Aβ1-42-treated PC12 cells.
本研究旨在验证胰高血糖素样肽-1 受体（GLP-1R）/环腺苷酸（cAMP）/蛋白激酶（PKA）/胰岛素降解酶（IDE）信号通路是否与神经元凋亡有关。我们通过将 APP/PS1 小鼠（AD 模型）与链脲佐菌素（STZ）处理的小鼠（T2D 模型）杂交，建立了一种同时患有阿尔茨海默病（AD）和 2 型糖尿病（T2D）的动物模型。通过 TUNEL 染色检测神经元凋亡，通过 Western blot 检测凋亡相关蛋白的表达水平。通过 MTT 分析检测 PC12 细胞活力，通过流式细胞术检测 PC12 细胞凋亡。通过 qRT-PCR 检测 mRNA 表达水平。T2D 通过促使神经元凋亡和增加促凋亡蛋白的表达来促进 AD 的进展。β-淀粉样肽 1-42（Aβ1-42）被证明对抑制 PC12 细胞活力和促进细胞凋亡有影响。然而，GLP-1R 激动剂栀子苷（Gen）显著逆转了这些作用，对 PC12 细胞发挥保护作用。IDE 拮抗剂杆菌肽（Bac）显著逆转了 Gen 对 Aβ1-42 处理的 PC12 细胞的保护作用。此外，Gen 显著逆转了 Aβ1-42 处理对 IDE 表达的影响，而 cAMP/PKA 信号通路抑制剂显著逆转了 Gen 对 Aβ1-42 处理的 PC12 细胞中 IDE 表达水平的影响。总之，GLP-1R 通过调节 cAMP/PKA/IDE 信号通路调节 Aβ1-42 处理的 PC12 细胞中的细胞生长，至少部分如此。
