Holubiec M I, Gellert M, Hanschmann E M
IBioBA-MPSP Instituto de Investigación en Biomedicina de Buenos Aires, Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
Institute for Medical Biochemistry and Molecular Biology, University Medicine Greifwald, University Greifswald, Greifswald, Germany.
Front Aging Neurosci. 2022 Nov 3;14:1003721. doi: 10.3389/fnagi.2022.1003721. eCollection 2022.
Reduction and oxidation reactions are essential for biochemical processes. They are part of metabolic pathways and signal transduction. Reactive oxygen species (ROS) as second messengers and oxidative modifications of cysteinyl (Cys) residues are key to transduce and translate intracellular and intercellular signals. Dysregulation of cellular redox signaling is known as oxidative distress, which has been linked to various pathologies, including neurodegeneration. Alzheimer's disease (AD) is a neurodegenerative pathology linked to both, abnormal amyloid precursor protein (APP) processing, generating Aβ peptide, and Tau hyperphosphorylation and aggregation. Signs of oxidative distress in AD include: increase of ROS (HO, O ), decrease of the levels or activities of antioxidant enzymes, abnormal oxidation of macromolecules related to elevated Aβ production, and changes in mitochondrial homeostasis linked to Tau phosphorylation. Interestingly, Cys residues present in APP form disulfide bonds that are important for intermolecular interactions and might be involved in the aggregation of Aβ. Moreover, two Cys residues in some Tau isoforms have been shown to be essential for Tau stabilization and its interaction with microtubules. Future research will show the complexities of Tau, its interactome, and the role that Cys residues play in the progression of AD. The specific modification of cysteinyl residues in redox signaling is also tightly connected to the regulation of various metabolic pathways. Many of these pathways have been found to be altered in AD, even at very early stages. In order to analyze the complex changes and underlying mechanisms, several AD models have been developed, including animal models, 2D and 3D cell culture, and studies of patient samples. The use of these models along with innovative, new redox analysis techniques are key to further understand the importance of the redox component in Alzheimer's disease and the identification of new therapeutic targets in the future.
还原和氧化反应对于生物化学过程至关重要。它们是代谢途径和信号转导的一部分。活性氧（ROS）作为第二信使以及半胱氨酰（Cys）残基的氧化修饰是转导和转化细胞内和细胞间信号的关键。细胞氧化还原信号失调被称为氧化应激，它与包括神经退行性变在内的各种病理状态相关。阿尔茨海默病（AD）是一种神经退行性病变，与异常的淀粉样前体蛋白（APP）加工产生Aβ肽以及Tau蛋白过度磷酸化和聚集均有关联。AD中氧化应激的迹象包括：ROS（羟基自由基、超氧阴离子）增加、抗氧化酶水平或活性降低、与Aβ产生增加相关的大分子异常氧化以及与Tau磷酸化相关的线粒体稳态变化。有趣的是，APP中存在的Cys残基形成二硫键，这些二硫键对于分子间相互作用很重要，并且可能参与Aβ的聚集。此外，一些Tau异构体中的两个Cys残基已被证明对于Tau的稳定及其与微管的相互作用至关重要。未来的研究将揭示Tau的复杂性、其相互作用组以及Cys残基在AD进展中所起的作用。氧化还原信号中半胱氨酰残基的特异性修饰也与各种代谢途径的调节紧密相关。已发现其中许多途径在AD中发生改变，甚至在非常早期阶段就已出现。为了分析这些复杂的变化及其潜在机制，已经开发了多种AD模型，包括动物模型、二维和三维细胞培养以及患者样本研究。使用这些模型以及创新的新型氧化还原分析技术是进一步了解氧化还原成分在阿尔茨海默病中的重要性以及未来识别新治疗靶点的关键。
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