López-Guerrero Victor E, Posadas Yanahi, Sánchez-López Carolina, Smart Amanda, Miranda Jael, Singewald Kevin, Bandala Yamir, Juaristi Eusebio, Den Auwer Christophe, Perez-Cruz Claudia, González-Mariscal Lorenza, Millhauser Glenn, Segovia Jose, Quintanar Liliana
Department of Physiology, Biophysics, and Neuroscience, Center for Research and Advanced Studies (Cinvestav), Mexico City 07360, Mexico.
Department of Chemistry, Center for Research and Advanced Studies (Cinvestav), Mexico City 07360, Mexico.
ACS Chem Neurosci. 2025 Jan 15;16(2):241-261. doi: 10.1021/acschemneuro.4c00796. Epub 2024 Dec 26.
Alzheimer's disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu-Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu binding to the cellular prion protein (PrP). Therefore, in addition to metal selectivity and blood-brain barrier (BBB) permeability, an emerging challenge for copper chelators is to prevent the formation of neurotoxic Cu-Aβ species without perturbing the neuroprotective Cu-PrP interaction. Previously, we reported the design of a tetrapeptide (TP) that withdraws Cu from Aβ(1-16) and impacts the Cu-induced aggregation of Aβ(1-40). In this study, we improved the drug-like properties of TP in a BBB model, evaluated the metal selectivity of the optimized peptide (TP*), and tested its effect on Cu coordination to PrP and proteins involved in copper trafficking, such as copper transporter 1 and albumin. Our results show that changing the stereochemistry of the first residue prevents TP degradation in the BBB model and coadministration of TP with a peptide that increases BBB permeability allows its passage through the BBB model. TP* is highly selective toward Cu in the presence of Zn ions, transfers Cu to copper-trafficking proteins, and forms a ternary TP*-Cu-PrP species that does not perturb the physiological conformation of PrP and displays only a minor impact in the neuroprotective Cu-dependent interaction of PrP with the -methyl-d-aspartate receptor. Overall, these results show that TP* displays desirable features for a copper chelator with therapeutic potential against AD. Moreover, this is the first study that explores the effect of a Cu chelator with therapeutic potential for AD on Cu coordination to PrP (an emerging key player in AD pathology), integrating recent knowledge about metalloproteins involved in AD with the design of copper chelators against AD.
阿尔茨海默病（AD）是全球最常见的痴呆形式。AD大脑的特征是淀粉样β肽（Aβ）的积累，Aβ可结合铜并与多种神经毒性机制相关。尽管有人提出使用铜螯合剂来预防Cu-Aβ复合物的形成作为一种治疗策略，但最近的研究表明，铜是一种重要的神经调节剂，对于由铜与细胞朊蛋白（PrP）结合介导的神经保护机制至关重要。因此，除了金属选择性和血脑屏障（BBB）通透性外，铜螯合剂面临的一个新挑战是在不干扰神经保护的Cu-PrP相互作用的情况下，防止神经毒性Cu-Aβ物种的形成。此前，我们报道了一种四肽（TP）的设计，该四肽可从Aβ(1-16)中提取铜，并影响铜诱导的Aβ(1-40)聚集。在本研究中，我们在BBB模型中改善了TP的类药物性质，评估了优化肽（TP*）的金属选择性，并测试了其对铜与PrP以及参与铜转运的蛋白质（如铜转运蛋白1和白蛋白）配位的影响。我们的结果表明，改变第一个残基的立体化学可防止TP在BBB模型中降解，并且将TP与增加BBB通透性的肽共同给药可使其通过BBB模型。TP在锌离子存在下对铜具有高度选择性，将铜转移至参与铜转运的蛋白质，并形成三元TP-Cu-PrP物种，该物种不会干扰PrP的生理构象，并且对PrP与N-甲基-D-天冬氨酸受体的神经保护铜依赖性相互作用仅产生轻微影响。总体而言，这些结果表明TP*对于具有治疗AD潜力的铜螯合剂具有理想的特性。此外，这是第一项探索具有治疗AD潜力的铜螯合剂对铜与PrP（AD病理学中一个新的关键参与者）配位影响的研究，将有关AD中涉及的金属蛋白的最新知识与抗AD铜螯合剂的设计相结合。
