Centre for Molecular Neuropathology, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Division of Neuroscience, Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK.
Eur J Neurosci. 2022 Nov;56(9):5428-5441. doi: 10.1111/ejn.15662. Epub 2022 Apr 9.
Necroptosis, or programmed necrosis, involves the kinase activity of receptor interacting kinases 1 and 3, the activation of the pseudokinase mixed lineage kinase domain-like and formation of a complex called the necrosome. It is one of the non-apoptotic cell death pathways that has gained interest in the recent years, especially as a neuronal cell death pathway occurring in Alzheimer's disease. In this review, we focus our discussion on the various molecular mechanisms that could trigger neuronal death through necroptosis and have been shown to play a role in Alzheimer's disease pathogenesis and neuroinflammation. We describe how each of these pathways, such as tumour necrosis factor signalling, reactive oxygen species, endosomal sorting complex, post-translational modifications and certain individual molecules, is dysregulated or activated in Alzheimer's disease, and how this dysregulation/activation could trigger necroptosis. At the cellular level, many of these molecular mechanisms and pathways may act in parallel to synergize with each other or inhibit one another, and changes in the balance between them may determine different cellular vulnerabilities at different disease stages. However, from a therapeutic standpoint, it remains unclear how best to target one or more of these pathways, given that such diverse pathways could all contribute to necroptotic cell death in Alzheimer's disease.
细胞程序性坏死，也称为程序性细胞坏死，涉及受体相互作用激酶 1 和 3 的激酶活性、假激酶混合谱系激酶结构域样蛋白的激活以及称为坏死体的复合物的形成。它是近年来受到关注的非凋亡细胞死亡途径之一，特别是作为阿尔茨海默病中发生的神经元细胞死亡途径。在这篇综述中，我们将讨论的重点放在各种分子机制上，这些机制可以通过坏死引起神经元死亡，并已被证明在阿尔茨海默病发病机制和神经炎症中发挥作用。我们描述了这些途径中的每一种，如肿瘤坏死因子信号、活性氧、内体分选复合物、翻译后修饰和某些单个分子，在阿尔茨海默病中是如何失调或激活的，以及这种失调/激活如何引发坏死。在细胞水平上，这些分子机制和途径中的许多可能并行作用，相互协同或相互抑制，它们之间的平衡变化可能决定不同疾病阶段的不同细胞脆弱性。然而，从治疗的角度来看，鉴于如此多样化的途径都可能导致阿尔茨海默病中的坏死性细胞死亡，尚不清楚如何最好地靶向这些途径中的一个或多个途径。
