Department of Biochemistry, University of Allahabad, Allahabad, 211002, India.
Department of Biomedical Engineering, National Institute of Technology, Raipur, 492010, India.
Neurotox Res. 2017 Oct;32(3):351-361. doi: 10.1007/s12640-017-9746-5. Epub 2017 May 8.
Autophagy is an evolutionary conserved catabolic process that ensures continuous removal of damaged cell organelles and long-lived protein aggregates to maintain cellular homeostasis. Although autophagy has been implicated in amyloid-β (Aβ) production and deposition, its role in pathogenesis of Alzheimer's disease remains elusive. Thus, the present study was undertaken to assess the cytoprotective and neuroprotective potential of autophagy on Aβ-induced oxidative stress, apoptosis and neurotoxicity in human neuroblastoma SH-SY5Y cells. The treatment of Aβ1-42 impaired the cell growth and redox balance, and induced apoptosis and neurotoxicity in SH-SY5Y cells. Next, the treatment of rapamycin (RAP) significantly elevated the expression of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), sequestosome-1/p62, Beclin-1, and unc-51-like kinase-1 (ULK1) in SH-SY5Y cells. RAP-induced activation of autophagy notably alleviated the Aβ1-42-induced impairment of redox balance by decreasing the levels of pro-oxidants such as reactive oxygen species, lipid peroxidation and Ca influx, and concurrently increasing the levels of antioxidant enzymes such as superoxide dismutase and catalase. The RAP-induced autophagy also ameliorated Aβ1-42-induced loss of mitochondrial membrane potential and apoptosis. Additionally, the activated autophagy provided significant neuroprotection against Aβ1-42-induced neurotoxicity by elevating the expression of neuronal markers such as synapsin-I, PSD95, NCAM, and CREB. However, 3-methyladenine treatment significantly exacerbated the neurotoxic effects of Aβ1-42. Taken together, our study demonstrated that the activation of autophagy provided possible neuroprotection against Aβ-induced cytotoxicity, oxidative stress, apoptosis, and neurotoxicity in SH-SY5Y neuronal cells.
自噬是一种进化上保守的分解代谢过程，可确保不断清除受损的细胞器和长寿蛋白聚集体，以维持细胞内环境稳定。尽管自噬与淀粉样β（Aβ）的产生和沉积有关，但它在阿尔茨海默病发病机制中的作用仍不清楚。因此，本研究旨在评估自噬对 Aβ诱导的人神经母细胞瘤 SH-SY5Y 细胞氧化应激、细胞凋亡和神经毒性的细胞保护和神经保护作用。Aβ1-42 的处理损害了细胞生长和氧化还原平衡，并诱导 SH-SY5Y 细胞发生细胞凋亡和神经毒性。接下来，雷帕霉素（RAP）的处理显著提高了自噬标志物的表达，如微管相关蛋白-1 轻链-3（LC3）、自噬相关蛋白 1（p62）、Beclin-1 和 UNC-51 样激酶-1（ULK1）在 SH-SY5Y 细胞中。RAP 诱导的自噬激活显著减轻了 Aβ1-42 诱导的氧化还原平衡损害，降低了活性氧、脂质过氧化和 Ca 内流等促氧化剂的水平，同时增加了超氧化物歧化酶和过氧化氢酶等抗氧化酶的水平。RAP 诱导的自噬还改善了 Aβ1-42 诱导的线粒体膜电位丧失和细胞凋亡。此外，激活的自噬通过提高神经元标志物如突触素-I、PSD95、NCAM 和 CREB 的表达，对 Aβ1-42 诱导的神经毒性提供了显著的神经保护作用。然而，3-甲基腺嘌呤处理显著加剧了 Aβ1-42 的神经毒性作用。总之，我们的研究表明，自噬的激活为 Aβ 诱导的 SH-SY5Y 神经元细胞毒性、氧化应激、细胞凋亡和神经毒性提供了可能的神经保护作用。
