Department of Anatomy and Neuroscience, College of Medicine, Eulji University, Daejeon, 34824, Republic of Korea.
Department of Pharmacology and Biomedical Sciences, College of Medicine, Seoul National University, 103 Daehakro, Jongro-gu, Seoul, Republic of Korea.
J Pharmacol Sci. 2018 Jun;137(2):146-153. doi: 10.1016/j.jphs.2018.05.004. Epub 2018 May 29.
The amyloid precursor protein (APP) is a key molecule in Alzheimer's disease. The prevailing view is that APP is initially transported to the plasma membrane as a full-length protein. Its localization at the cell surface can trigger downstream signaling and APP cleavage. Our previous work has shown that Neuregulin 1 (NRG1) has neuroprotective effects in an Alzheimer's disease model. In the present study, we examine whether NRG1 signaling is involved in APP expression and non-amyloidogenic processing in neuronal cells. Here we show that NRG1 increased the cell surface expression of APP without changing the total amount of APP mRNA or protein expression in SH-SY5Y cells and in rat primary cortical neurons. In addition, NRG1 significantly increased the levels of the secreted form of APP, sAPPα, in the conditioned media but did not change the expression of ADAM10 on the cell surface or in the cell lysates. Furthermore, we found that the protein level of NRG1 was reduced in the hippocampus of Alzheimer's disease (AD) patients. Our results demonstrate that NRG1 increased APP expression on the cell surface and sAPPα secretion into the media of neuronal cell cultures. Taken together, these results suggest a role for NRG1 in non-amyloidogenic processing.
淀粉样前体蛋白（APP）是阿尔茨海默病的关键分子。目前的观点认为，APP 最初作为全长蛋白被运输到质膜。其在细胞表面的定位可以触发下游信号和 APP 切割。我们之前的工作表明，神经调节蛋白 1（NRG1）在阿尔茨海默病模型中具有神经保护作用。在本研究中，我们研究了 NRG1 信号是否参与神经元细胞中的 APP 表达和非淀粉样生成处理。在这里，我们发现 NRG1 增加了 SH-SY5Y 细胞和大鼠原代皮质神经元中 APP 的细胞表面表达，而不改变 APP mRNA 或蛋白表达的总量。此外，NRG1 显著增加了条件培养基中 sAPPα的分泌形式的水平，但不改变细胞表面或细胞裂解物中 ADAM10 的表达。此外，我们发现阿尔茨海默病（AD）患者海马体中的 NRG1 蛋白水平降低。我们的结果表明，NRG1 增加了神经元细胞培养物中 APP 的细胞表面表达和 sAPPα 的分泌。总之，这些结果表明 NRG1 在非淀粉样生成处理中起作用。
