{"title":"与阿尔茨海默病相关的血红素和铜β的氧化应激和神经毒性机制","authors":"Chinmay Dey, Madhuparna Roy, Puja Pal, Rimi Ghosh, Somdatta Ghosh Dey","doi":"10.1039/d5cs00544b","DOIUrl":null,"url":null,"abstract":"Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathophysiology involving oxidative stress, amyloid β (Aβ) aggregation and dysregulation of metal ions, particularly copper and heme. The overproduction of reactive oxygen species (ROS) plays a crucial role in the early stages of AD, leading to lipid peroxidation, protein oxidation, nucleic acid damage and neurotransmitter oxidation. These oxidative processes are further catalysed by the accumulation of Aβ peptides, which increase ROS production, creating a self-perpetuating cycle that accelerates disease progression. This review focuses on the critical role of oxidative stress and neurotoxicity associated with heme and copper in AD pathology. Both the metal and the co-factor bind to Aβ peptides, forming complexes that amplify oxidative stress, leading to enhanced neuronal damage. The involvement of Cu/heme–Aβ complexes in redox cycling results in the production of cytotoxic hydrogen peroxide, which drives the oxidation of neurotransmitters and contributes to synaptic dysfunction. These interactions not only disrupt normal neuronal function but also intensify Aβ plaque formation, a key feature of AD progression. Understanding how heme and copper interact with Aβ, and how these interactions are influenced by important residues such as histidine, arginine and tyrosine is crucial. These amino acids play an essential role in metal coordination and in regulating the reactivity of metal/co-factor-Aβ complexes, which directly impacts neuronal health. Unveiling the interactions between Aβ peptides and Cu/heme as well as the associated oxidative reactions offers a promising direction for future research, potentially leading to strategies that mitigate oxidative stress and reduce cytotoxicity in Alzheimer's disease.","PeriodicalId":68,"journal":{"name":"Chemical Society Reviews","volume":"24 1","pages":""},"PeriodicalIF":39.0000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanism of oxidative stress and neurotoxicity associated with heme and copper–Aβ relevant to Alzheimer's disease\",\"authors\":\"Chinmay Dey, Madhuparna Roy, Puja Pal, Rimi Ghosh, Somdatta Ghosh Dey\",\"doi\":\"10.1039/d5cs00544b\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathophysiology involving oxidative stress, amyloid β (Aβ) aggregation and dysregulation of metal ions, particularly copper and heme. The overproduction of reactive oxygen species (ROS) plays a crucial role in the early stages of AD, leading to lipid peroxidation, protein oxidation, nucleic acid damage and neurotransmitter oxidation. These oxidative processes are further catalysed by the accumulation of Aβ peptides, which increase ROS production, creating a self-perpetuating cycle that accelerates disease progression. This review focuses on the critical role of oxidative stress and neurotoxicity associated with heme and copper in AD pathology. Both the metal and the co-factor bind to Aβ peptides, forming complexes that amplify oxidative stress, leading to enhanced neuronal damage. The involvement of Cu/heme–Aβ complexes in redox cycling results in the production of cytotoxic hydrogen peroxide, which drives the oxidation of neurotransmitters and contributes to synaptic dysfunction. These interactions not only disrupt normal neuronal function but also intensify Aβ plaque formation, a key feature of AD progression. Understanding how heme and copper interact with Aβ, and how these interactions are influenced by important residues such as histidine, arginine and tyrosine is crucial. These amino acids play an essential role in metal coordination and in regulating the reactivity of metal/co-factor-Aβ complexes, which directly impacts neuronal health. Unveiling the interactions between Aβ peptides and Cu/heme as well as the associated oxidative reactions offers a promising direction for future research, potentially leading to strategies that mitigate oxidative stress and reduce cytotoxicity in Alzheimer's disease.\",\"PeriodicalId\":68,\"journal\":{\"name\":\"Chemical Society Reviews\",\"volume\":\"24 1\",\"pages\":\"\"},\"PeriodicalIF\":39.0000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Society Reviews\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1039/d5cs00544b\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Society Reviews","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d5cs00544b","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
阿尔茨海默病(AD)是一种神经退行性疾病,具有复杂的病理生理,涉及氧化应激、β淀粉样蛋白(a β)聚集和金属离子(特别是铜和血红素)的失调。活性氧(ROS)的过量产生在AD的早期阶段起着至关重要的作用,导致脂质过氧化、蛋白质氧化、核酸损伤和神经递质氧化。这些氧化过程被a β肽的积累进一步催化,从而增加ROS的产生,形成一个自我延续的循环,加速疾病进展。本文综述了氧化应激和与血红素和铜相关的神经毒性在AD病理中的关键作用。金属和辅助因子都与Aβ肽结合,形成复合物,放大氧化应激,导致神经元损伤加剧。Cu/血红素- α β复合物参与氧化还原循环导致细胞毒性过氧化氢的产生,过氧化氢驱动神经递质氧化并导致突触功能障碍。这些相互作用不仅破坏了正常的神经元功能,而且还加强了a β斑块的形成,这是AD进展的一个关键特征。了解血红素和铜如何与Aβ相互作用,以及这些相互作用如何受到组氨酸、精氨酸和酪氨酸等重要残基的影响是至关重要的。这些氨基酸在金属配位和调节金属/辅因子- a β复合物的反应性中发挥重要作用,直接影响神经元的健康。揭示a β肽与Cu/血红素之间的相互作用以及相关的氧化反应为未来的研究提供了一个有希望的方向,可能导致减轻阿尔茨海默病氧化应激和降低细胞毒性的策略。
Mechanism of oxidative stress and neurotoxicity associated with heme and copper–Aβ relevant to Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathophysiology involving oxidative stress, amyloid β (Aβ) aggregation and dysregulation of metal ions, particularly copper and heme. The overproduction of reactive oxygen species (ROS) plays a crucial role in the early stages of AD, leading to lipid peroxidation, protein oxidation, nucleic acid damage and neurotransmitter oxidation. These oxidative processes are further catalysed by the accumulation of Aβ peptides, which increase ROS production, creating a self-perpetuating cycle that accelerates disease progression. This review focuses on the critical role of oxidative stress and neurotoxicity associated with heme and copper in AD pathology. Both the metal and the co-factor bind to Aβ peptides, forming complexes that amplify oxidative stress, leading to enhanced neuronal damage. The involvement of Cu/heme–Aβ complexes in redox cycling results in the production of cytotoxic hydrogen peroxide, which drives the oxidation of neurotransmitters and contributes to synaptic dysfunction. These interactions not only disrupt normal neuronal function but also intensify Aβ plaque formation, a key feature of AD progression. Understanding how heme and copper interact with Aβ, and how these interactions are influenced by important residues such as histidine, arginine and tyrosine is crucial. These amino acids play an essential role in metal coordination and in regulating the reactivity of metal/co-factor-Aβ complexes, which directly impacts neuronal health. Unveiling the interactions between Aβ peptides and Cu/heme as well as the associated oxidative reactions offers a promising direction for future research, potentially leading to strategies that mitigate oxidative stress and reduce cytotoxicity in Alzheimer's disease.
期刊介绍:
Chemical Society Reviews is published by: Royal Society of Chemistry.
Focus: Review articles on topics of current interest in chemistry;
Predecessors: Quarterly Reviews, Chemical Society (1947–1971);
Current title: Since 1971;
Impact factor: 60.615 (2021);
Themed issues: Occasional themed issues on new and emerging areas of research in the chemical sciences