Filiz Gulay, Price Katherine A, Caragounis Aphrodite, Du Tai, Crouch Peter J, White Anthony R
Department of Pathology and the Centre for Neuroscience, The University of Melbourne, Melbourne, VIC 3010, Australia.
Eur Biophys J. 2008 Mar;37(3):315-21. doi: 10.1007/s00249-007-0244-1. Epub 2008 Feb 13.
Biometals such as copper and zinc have an important role in Alzheimer's disease (AD). Accumulating evidence indicates that copper homeostasis is altered in AD brain with elevated extracellular and low intracellular copper levels. Studies in animals and cell cultures have suggested that increasing intracellular copper can ameliorate AD-like pathology including amyloid deposition and tau phosphorylation. Modulating copper homeostasis can also improve cognitive function in animal models of AD. Treatments are now being developed that may result in redistribution of copper within the brain. Metal ligands such as clioquinol (CQ), DP-109 or pyrrolidine dithiocarbamate (PDTC) have shown promising results in animal models of AD, however, the actual mode of action in vivo has not been fully determined. We previously reported that CQ-metal complexes were able to increase intracellular copper levels in vitro. This resulted in stimulation of phosphoinositol-3-kinase activity and mitogen activated protein kinases (MAPK). Increased kinase activity resulted in up-regulated matrix metalloprotease (MMP2 and MMP3) activity resulting in enhanced degradation of secreted A beta. These findings are consistent with previous studies reporting metal-mediated activation of MAPKs and MMPs. How this activation occurs is unknown but evidence suggests that copper may be able to activate membrane receptors such as the epidermal growth factor receptor (EGFR) and result in downstream activation of MAPK pathways. This has been supported by studies showing metal-mediated activation of EGFR through ligand-independent processes in a number of cell-types. Our initial studies reveal that copper complexes can in fact activate EGFR. However, further studies are necessary to determine if metal complexes such as CQ-copper induce up-regulation of A beta-degrading MMP activity through this mechanism. Elucidation of this pathway may have important implications for the development of metal ligand based therapeutics for treatment of AD and other neurodegenerative disorders.
铜和锌等生物金属在阿尔茨海默病（AD）中起着重要作用。越来越多的证据表明，AD大脑中的铜稳态发生改变，细胞外铜水平升高而细胞内铜水平降低。动物和细胞培养研究表明，增加细胞内铜可以改善AD样病理，包括淀粉样蛋白沉积和tau蛋白磷酸化。调节铜稳态还可以改善AD动物模型的认知功能。目前正在开发的治疗方法可能会导致大脑内铜的重新分布。金属配体如氯碘羟喹（CQ）、DP-109或吡咯烷二硫代氨基甲酸盐（PDTC）在AD动物模型中已显示出有前景的结果，然而，其体内实际作用模式尚未完全确定。我们之前报道过CQ-金属复合物能够在体外增加细胞内铜水平。这导致磷酸肌醇-3-激酶活性和丝裂原活化蛋白激酶（MAPK）受到刺激。激酶活性增加导致基质金属蛋白酶（MMP2和MMP3）活性上调，从而增强分泌型Aβ 的降解。这些发现与之前报道金属介导的MAPK和MMPs激活的研究一致。这种激活是如何发生的尚不清楚，但有证据表明铜可能能够激活膜受体，如表皮生长因子受体（EGFR），并导致MAPK途径的下游激活。这已得到多项研究的支持，这些研究表明在多种细胞类型中金属通过非配体依赖过程介导EGFR的激活。我们的初步研究表明铜复合物实际上可以激活EGFR。然而，需要进一步研究以确定诸如CQ-铜等金属复合物是否通过这种机制诱导Aβ 降解MMP活性的上调。阐明这一途径可能对开发基于金属配体的AD和其他神经退行性疾病治疗方法具有重要意义。
