Chen Li-Lin, Fan Yong-Gang, Zhao Ling-Xiao, Zhang Qi, Wang Zhan-You
Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang 110122, China.
Bioorg Chem. 2023 Feb;131:106301. doi: 10.1016/j.bioorg.2022.106301. Epub 2022 Nov 25.
Alzheimer's disease (AD), characterized by the β-amyloid protein (Aβ) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aβ monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aβ deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aβ but also directly bind to Aβ and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aβ dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.
阿尔茨海默病（AD）以β-淀粉样蛋白（Aβ）沉积和tau蛋白过度磷酸化为特征，是病因不明的最常见痴呆症。Aβ单克隆抗体药物的临床试验几乎都失败了，这使得人们对AD的其他病因假说，如金属离子代谢紊乱和慢性神经炎症，给予了极大关注。越来越多的证据表明，AD患者易感脑区的金属离子（铁、铜和锌）失调，这与Aβ沉积、tau蛋白过度磷酸化、神经元丢失以及神经炎症高度相关。进一步的研究发现，铁、铜和锌不仅可以增强Aβ的产生，还可以直接与Aβ和tau蛋白结合，促进它们的聚集。此外，铁和铜的积累分别可以促进铁死亡和铜死亡。因此，金属离子螯合剂被认为是治疗AD的有前景的药物。这篇综述全面总结了金属离子在AD进展过程中对Aβ动态变化和tau蛋白磷酸化的影响。此外，鉴于慢性神经炎症促进AD的进展，我们还总结了金属离子与神经炎症相关的机制，并强调金属离子螯合剂可能是在AD情况下减轻神经炎症的潜在药物。然而，关于金属离子对神经炎症的更多研究仍需开展，金属离子螯合剂对神经炎症的影响应得到更多关注。标题：对抗神经炎症金属螯合剂
