Abstract： Objective mTOR signaling pathway plays an important role in Aβ mediated-neurodegenerative disorders. As the mTOR inhibitor, rapamycin is a potentially being therapeutic drug. This study aims to evaluate the effect of FIM-X7, a novel rapamycin derivative containing a thiazole side chain, on Aβ expression level in N2a-APP695 cells and provide an insight to its application in Alzheimer’s disease. Methods The effects of FIM-X7 on Aβ40 and Aβ42 in N2a-APP695 cells were measured by ELISA. The expression level of autophagy related proteins and mTOR signaling pathway under the treatment of FIM-X7 were detected by Western blot. Lymphocyte transformation test was conducted to determine the immunosuppressive activity of FIM-X7, MTT assay and flow cytometry were performed to determine the cell proliferation and apoptosis respectively. Results FIM-X7 exhibited reduction on the expression of Aβ40 and Aβ42 through the inhibition of mTOR signaling pathway and down-regulation of the phosphorylation of ULK1. The efficacy of FIM-X7 in N2a-APP695 cells was comparable to rapamycin. No obvious cytotoxicity of FIM-X7 was found in our study. The inhibition effect of mice spleen lymphocyte transformation induced by ConA was only 1/5000 compared to rapamycin. Conclusion As a novel rapamycin derivative, FIM-X7 showed reduction on the expression of Aβ40 and Aβ42 in N2a-APP695 cells, and displayed lower immunosuppressive activity as well as cytotoxicity compared with rapamycin. Therefore, it is worthy of exploring the therapeutic prospect of FIM-X7 on the treatment of alzheimer's disease in future studies.
李夸良 吕裕斌 谢立君 应加银 余辉 程元荣 潘福生 黄捷. 雷帕霉素新衍生物FIM-X7通过促进自噬影响N2a-APP695细胞表达β淀粉样蛋白的研究#br#[J]. 中国抗生素杂志, 2020, 45(08): 763-768.
Li Kua-liang, Lü Yu-bin, Xie Li-jun, Ying Jia-yin, Yu Hui, Cheng Yuan-rong, Pan Fu-sheng and Huang Jie. Research on the influence of novel rapamycin derivative FIM-X7 upon the expression of amyloid β-peptide in N2a-APP695 cells via promoting autophagy. CJA, 2020, 45(08): 763-768.