放弃阿尔茨海默病中铜离子治疗性螯合的理由。
The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.
作者信息
Drew Simon C
机构信息
Department of Medicine, Royal Melbourne Hospital, University of MelbourneMelbourne, VIC, Australia.
出版信息
Front Neurosci. 2017 Jun 2;11:317. doi: 10.3389/fnins.2017.00317. eCollection 2017.
Abstract
The "therapeutic chelation" approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with the premise that small molecules can be designed to prevent transition metal-induced amyloid deposition and oxidative stress within the AD brain. Over more than 20 years, countless studies have been devoted to characterizing metal binding, its effect on Aβ aggregation, ROS production, and toxicity. Despite a lack of evidence for any clinical benefit, the conjecture that therapeutic chelation is an effective approach for treating AD remains widespread. Here, the author plays the devil's advocate, questioning the experimental evidence, the dogma, and the value of therapeutic chelation, with a major focus on copper ions.
摘要
治疗阿尔茨海默病（AD）的“治疗性螯合”方法源自金属假说，其前提是可以设计小分子来预防过渡金属诱导的AD脑内淀粉样蛋白沉积和氧化应激。20多年来，无数研究致力于表征金属结合、其对Aβ聚集、活性氧生成和毒性的影响。尽管缺乏任何临床益处的证据，但治疗性螯合是治疗AD的有效方法这一推测仍然广泛存在。在此，作者唱唱反调，质疑实验证据、教条以及治疗性螯合的价值，主要聚焦于铜离子。
相似文献
1
The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease.放弃阿尔茨海默病中铜离子治疗性螯合的理由。
Front Neurosci. 2017 Jun 2;11:317. doi: 10.3389/fnins.2017.00317. eCollection 2017.
2
Copper Toxicity Links to Pathogenesis of Alzheimer's Disease and Therapeutics Approaches.铜毒性与阿尔茨海默病发病机制的关联及治疗方法。
Int J Mol Sci. 2020 Oct 16;21(20):7660. doi: 10.3390/ijms21207660.
3
Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer's disease: Limitations, and current and future perspectives.金属生物学与生物金属（铜、锌和铁）在阿尔茨海默病中的治疗螯合作用：局限性，以及当前和未来的展望。
J Trace Elem Med Biol. 2021 Sep;67:126779. doi: 10.1016/j.jtemb.2021.126779. Epub 2021 May 15.
4
Copper-mediated β-amyloid toxicity and its chelation therapy in Alzheimer's disease.铜介导的β-淀粉样蛋白毒性及其在阿尔茨海默病中的螯合治疗。
Metallomics. 2022 Jun 13;14(6). doi: 10.1093/mtomcs/mfac018.
5
Bifunctional backbone modified squaramide dipeptides as amyloid beta (Aβ) aggregation inhibitors.双功能主链修饰的瓜环二肽作为淀粉样β（Aβ）聚集抑制剂。
Bioorg Med Chem. 2024 Jan 1;97:117538. doi: 10.1016/j.bmc.2023.117538. Epub 2023 Nov 30.
6
Metal Ions in Alzheimer's Disease: A Key Role or Not?金属离子在阿尔茨海默病中的作用：关键还是不关键？
Acc Chem Res. 2019 Jul 16;52(7):2026-2035. doi: 10.1021/acs.accounts.9b00248. Epub 2019 Jul 5.
7
Challenges and Opportunities of Metal Chelation Therapy in Trace Metals Overload-Induced Alzheimer's Disease.金属螯合疗法在微量元素超负荷诱导的阿尔茨海默病中的挑战与机遇。
Neurotox Res. 2023 Jun;41(3):270-287. doi: 10.1007/s12640-023-00634-7. Epub 2023 Jan 27.
8
The ongoing search for small molecules to study metal-associated amyloid-β species in Alzheimer's disease.正在寻找小分子以研究阿尔茨海默病中与金属相关的淀粉样-β 物种。
Acc Chem Res. 2014 Aug 19;47(8):2475-82. doi: 10.1021/ar500152x. Epub 2014 Jul 31.
9
Amyloid-beta metal interaction and metal chelation.淀粉样β蛋白与金属的相互作用及金属螯合作用。
Subcell Biochem. 2005;38:235-54. doi: 10.1007/0-387-23226-5_12.
10
Regulatory Activities of Dopamine and Its Derivatives toward Metal-Free and Metal-Induced Amyloid-β Aggregation, Oxidative Stress, and Inflammation in Alzheimer's Disease.多巴胺及其衍生物对阿尔茨海默病中非金属诱导和金属诱导的β淀粉样蛋白聚集、氧化应激和炎症的调节作用。
ACS Chem Neurosci. 2018 Nov 21;9(11):2655-2666. doi: 10.1021/acschemneuro.8b00122. Epub 2018 Jun 8.
引用本文的文献
1
Copper homeostasis and cuproptosis in Alzheimer's disease (Review).阿尔茨海默病中的铜稳态与铜死亡（综述）
Int J Mol Med. 2025 Nov;56(5). doi: 10.3892/ijmm.2025.5613. Epub 2025 Aug 24.
2
Human Trace Elements, Gut Microbiota, and Alzheimer's Disease: Insights From Multistage Mendelian Randomization Analysis.人类微量元素、肠道微生物群与阿尔茨海默病：多阶段孟德尔随机化分析的见解
Food Sci Nutr. 2025 Aug 12;13(8):e70706. doi: 10.1002/fsn3.70706. eCollection 2025 Aug.
3
Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition.阿尔茨海默病的多靶点导向治疗策略：控制淀粉样β蛋白聚集、金属离子稳态及酶抑制
Chem Sci. 2025 Jan 6;16(5):2105-2135. doi: 10.1039/d4sc06762b. eCollection 2025 Jan 29.
4
A Copper-Binding Peptide with Therapeutic Potential against Alzheimer's Disease: From the Blood-Brain Barrier to Metal Competition.一种具有治疗阿尔茨海默病潜力的铜结合肽：从血脑屏障到金属竞争
ACS Chem Neurosci. 2025 Jan 15;16(2):241-261. doi: 10.1021/acschemneuro.4c00796. Epub 2024 Dec 26.
5
Copper homeostasis and neurodegenerative diseases.铜稳态与神经退行性疾病
Neural Regen Res. 2025 Nov 1;20(11):3124-3143. doi: 10.4103/NRR.NRR-D-24-00642. Epub 2024 Nov 13.
6
MAD-microbial (origin of) Alzheimer's disease hypothesis: from infection and the antimicrobial response to disruption of key copper-based systems.MAD-微生物（起源的）阿尔茨海默病假说：从感染和抗菌反应到关键铜基系统的破坏
Front Neurosci. 2024 Oct 2;18:1467333. doi: 10.3389/fnins.2024.1467333. eCollection 2024.
7
Nanostructure and dynamics of N-truncated copper amyloid-β peptides from advanced X-ray absorption fine structure.基于先进X射线吸收精细结构的N端截短型铜淀粉样β肽的纳米结构与动力学
IUCrJ. 2024 May 1;11(Pt 3):325-346. doi: 10.1107/S2052252524001830.
8
Computational Study of Amyloidβ Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors.淀粉样β蛋白家族突变与金属相互作用的计算研究：对单体和聚集体动力学行为的影响
Inorg Chem. 2024 Mar 11;63(10):4725-4737. doi: 10.1021/acs.inorgchem.3c04555. Epub 2024 Feb 26.
9
Impact of aging on copper isotopic composition in the murine brain.衰老对小鼠大脑中铜同位素组成的影响。
Metallomics. 2024 May 2;16(5). doi: 10.1093/mtomcs/mfae008.
10
Molecular Insights into Cu/Zn Metal Response to the Amyloid β-Peptide (1-42).铜/锌金属对淀粉样β肽（1-42）反应的分子见解
ACS Phys Chem Au. 2023 Oct 25;4(1):57-66. doi: 10.1021/acsphyschemau.3c00041. eCollection 2024 Jan 24.
本文引用的文献
1
Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer's disease.快速进展型和散发性阿尔茨海默病中淀粉样斑块的蛋白质组学差异
Acta Neuropathol. 2017 Jun;133(6):933-954. doi: 10.1007/s00401-017-1691-0. Epub 2017 Mar 4.
2
Numerical Simulations Reveal Randomness of Cu(II) Induced Aβ Peptide Dimerization under Conditions Present in Glutamatergic Synapses.数值模拟揭示了在谷氨酸能突触存在的条件下铜（II）诱导Aβ肽二聚化的随机性。
PLoS One. 2017 Jan 26;12(1):e0170749. doi: 10.1371/journal.pone.0170749. eCollection 2017.
3
Iron, Copper, and Zinc Concentration in Aβ Plaques in the APP/PS1 Mouse Model of Alzheimer's Disease Correlates with Metal Levels in the Surrounding Neuropil.阿尔茨海默病 APP/PS1 小鼠模型中 Aβ 斑块中的铁、铜和锌浓度与周围神经突中的金属水平相关。
ACS Chem Neurosci. 2017 Mar 15;8(3):629-637. doi: 10.1021/acschemneuro.6b00362. Epub 2016 Dec 22.
4
Changes in intracellular copper concentration and copper-regulating gene expression after PC12 differentiation into neurons.PC12 分化为神经元后细胞内铜浓度和铜调节基因表达的变化。
Sci Rep. 2016 Sep 13;6:33007. doi: 10.1038/srep33007.
5
Copper Exchange and Redox Activity of a Prototypical 8-Hydroxyquinoline: Implications for Therapeutic Chelation.典型8-羟基喹啉的铜交换与氧化还原活性：对治疗性螯合的意义
Inorg Chem. 2016 Aug 1;55(15):7317-9. doi: 10.1021/acs.inorgchem.6b00832. Epub 2016 Jul 13.
6
A 2-Substituted 8-Hydroxyquinoline Stimulates Neural Stem Cell Proliferation by Modulating ROS Signalling.一种2-取代的8-羟基喹啉通过调节活性氧信号促进神经干细胞增殖。
Cell Biochem Biophys. 2016 Sep;74(3):297-306. doi: 10.1007/s12013-016-0747-4. Epub 2016 Jun 21.
7
Alzheimer's disease due to loss of function: A new synthesis of the available data.功能丧失所致阿尔茨海默病：现有数据的新综合分析
Prog Neurobiol. 2016 Aug;143:36-60. doi: 10.1016/j.pneurobio.2016.06.004. Epub 2016 Jun 18.
8
Resistance of Cu(Aβ4-16) to Copper Capture by Metallothionein-3 Supports a Function for the Aβ4-42 Peptide as a Synaptic Cu(II) Scavenger.金属硫蛋白-3对 Cu(Aβ4-16)的铜捕获抗性支持 Aβ4-42 肽作为突触 Cu(II)清除剂的功能。
Angew Chem Int Ed Engl. 2016 Jul 11;55(29):8235-8. doi: 10.1002/anie.201511968. Epub 2016 May 30.
9
Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease.在阿尔茨海默病的小鼠和线虫模型中，β淀粉样肽可抵御微生物感染。
Sci Transl Med. 2016 May 25;8(340):340ra72. doi: 10.1126/scitranslmed.aaf1059.
10
On the ability of CuAβ1-x peptides to form ternary complexes: Neurotransmitter glutamate is a competitor while not a ternary partner.关于CuAβ1-x肽形成三元复合物的能力：神经递质谷氨酸是竞争者而非三元复合物的组成部分。
J Inorg Biochem. 2016 May;158:5-10. doi: 10.1016/j.jinorgbio.2016.02.035. Epub 2016 Mar 2.
Zotero 插件