The pathology of sporadic Alzheimer's disease is hallmarked by altered signal transduction via the neurotransmitter receptor-G-protein-mediated protein kinase A (PKA) and protein kinase C (PKC) pathways. Because the accumulation of amyloid-β (Aβ) depends on its rates of synthesis and clearance, the metabolic pathway of Aβ in the brain and the entire body warrants exploration. The two major enzymes involved in Aβ degradation in the brain are believed to be the neprilysin and insulin-degrading enzyme (IDE). This study investigated whether PKA and PKC regulate the degradation of Aβ by modulating the protein levels of neprilysin and IDE in astrocytes. Activation of PKA induced a significant decrease in neprilysin protein levels in cultured astrocytes, whereas activation of PKC induced a significant decrease in the protein level of neprilysin and an increase in the protein level of IDE. Following activation of PKC, the reduction of neprilysin was achieved by its secretion into the culture media. Moreover, PKA-activated astrocytes significantly delayed the degradation of exogenous Aβ, whereas PKC-activated astrocytes significantly facilitated its degradation. These results suggest that PKA and PKC regulate Aβ degradation in astrocytes through a decrease in the protein level of neprilysin and an increase in neprilysin secretion and protein levels of IDE, respectively.

中文翻译：

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蛋白激酶 A 和 C 通过调节星形胶质细胞中脑啡肽酶和胰岛素降解酶的蛋白质水平来调节淀粉样蛋白-β 的降解

散发性阿尔茨海默病的病理学特征是通过神经递质受体-G-蛋白介导的蛋白激酶 A (PKA) 和蛋白激酶 C (PKC) 通路改变信号转导。由于淀粉样蛋白-β (Aβ) 的积累取决于其合成和清除率，因此 Aβ 在大脑和全身的代谢途径值得探索。参与大脑中 Aβ 降解的两种主要酶被认为是中性溶酶和胰岛素降解酶 (IDE)。本研究调查了 PKA 和 PKC 是否通过调节星形胶质细胞中脑啡肽酶和 IDE 的蛋白质水平来调节 Aβ 的降解。PKA 的激活导致培养的星形胶质细胞中的中性溶酶蛋白水平显着降低，而 PKC 的激活导致中性溶酶蛋白水平显着降低和 IDE 蛋白水平升高。在激活 PKC 后，通过分泌到培养基中实现中性溶酶的减少。此外，PKA 激活的星形胶质细胞显着延迟了外源 Aβ 的降解，而 PKC 激活的星形胶质细胞显着促进了其降解。这些结果表明，PKA 和 PKC 分别通过降低中性溶酶蛋白水平和增加中性溶酶分泌和 IDE 蛋白水平来调节星形胶质细胞中的 Aβ 降解。PKA 激活的星形胶质细胞显着延迟了外源 Aβ 的降解，而 PKC 激活的星形胶质细胞显着促进了其降解。这些结果表明，PKA 和 PKC 分别通过降低中性溶酶蛋白水平和增加中性溶酶分泌和 IDE 蛋白水平来调节星形胶质细胞中的 Aβ 降解。PKA 激活的星形胶质细胞显着延迟了外源 Aβ 的降解，而 PKC 激活的星形胶质细胞显着促进了其降解。这些结果表明，PKA 和 PKC 分别通过降低中性溶酶蛋白水平和增加中性溶酶分泌和 IDE 蛋白水平来调节星形胶质细胞中的 Aβ 降解。