School of Postgraduate Studies and Research, International Medical University, Kuala Lumpur, Malaysia.
Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur, Malaysia.
J Cell Mol Med. 2022 Mar;26(5):1434-1444. doi: 10.1111/jcmm.17095. Epub 2022 Feb 2.
Alzheimer's disease (AD), the major cause of dementia, affects the elderly population worldwide. Previous studies have shown that depletion of receptor-interacting protein kinase 1 (RIPK1) expression reverted the AD phenotype in murine AD models. Necroptosis, executed by mixed lineage kinase domain-like (MLKL) protein and activated by RIPK1 and RIPK3, has been shown to be involved in AD. However, the role of RIPK1 in beta-amyloid (Aβ)-induced necroptosis is not yet fully understood. In this study, we explored the role of RIPK1 in the SH-SY5Y human neuroblastoma cells treated with Aβ 1-40 or Aβ 1-42. We showed that Aβ-induced neuronal cell death was independent of apoptosis and autophagy pathways. Further analyses depicted that activation of RIPK1/MLKL-dependant necroptosis pathway was observed in vitro. We demonstrated that inhibition of RIPK1 expression rescued the cells from Aβ-induced neuronal cell death and ectopic expression of RIPK1 was found to enhance the stability of the endogenous APP. In summary, our findings demonstrated that Aβ can potentially drive necroptosis in an RIPK1-MLKL-dependent manner, proposing that RIPK1 plays an important role in the pathogenesis of AD.
阿尔茨海默病（AD）是痴呆症的主要病因，影响着全球的老年人群体。先前的研究表明，受体相互作用蛋白激酶 1（RIPK1）表达的耗竭可使 AD 小鼠模型的表型逆转。已证实由混合谱系激酶结构域样（MLKL）蛋白执行、由 RIPK1 和 RIPK3 激活的坏死性凋亡与 AD 有关。然而，RIPK1 在β-淀粉样蛋白（Aβ）诱导的坏死性凋亡中的作用尚未完全阐明。在这项研究中，我们探讨了 RIPK1 在 Aβ 1-40 或 Aβ 1-42 处理的 SH-SY5Y 人神经母细胞瘤细胞中的作用。结果表明，Aβ诱导的神经元细胞死亡不依赖于细胞凋亡和自噬途径。进一步的分析表明，体外观察到 RIPK1/MLKL 依赖性坏死性凋亡途径的激活。结果显示，抑制 RIPK1 表达可挽救 Aβ诱导的神经元细胞死亡，而过表达 RIPK1 可增强内源性 APP 的稳定性。总之，我们的研究结果表明，Aβ 可能以 RIPK1-MLKL 依赖的方式驱动坏死性凋亡，这表明 RIPK1 在 AD 的发病机制中发挥着重要作用。
