{"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}
引用次数: 0
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.
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