Caragounis Aphrodite, Du Tai, Filiz Gulay, Laughton Katrina M, Volitakis Irene, Sharples Robyn A, Cherny Robert A, Masters Colin L, Drew Simon C, Hill Andrew F, Li Qiao-Xin, Crouch Peter J, Barnham Kevin J, White Anthony R
Department of Pathology, The University of Melbourne, Victoria 3010, Australia.
Biochem J. 2007 Nov 1;407(3):435-50. doi: 10.1042/BJ20070579.
Biometals have an important role in AD (Alzheimer's disease) and metal ligands have been investigated as potential therapeutic agents for treatment of AD. In recent studies the 8HQ (8-hydroxyquinoline) derivative CQ (clioquinol) has shown promising results in animal models and small clinical trials; however, the actual mode of action in vivo is still being investigated. We previously reported that CQ-metal complexes up-regulated MMP (matrix metalloprotease) activity in vitro by activating PI3K (phosphoinositide 3-kinase) and JNK (c-jun N-terminal kinase), and that the increased MMP activity resulted in enhanced degradation of secreted Abeta (amyloid beta) peptide. In the present study, we have further investigated the biochemical mechanisms by which metal ligands affect Abeta metabolism. To achieve this, we measured the effects of diverse metal ligands on cellular metal uptake and secreted Abeta levels in cell culture. We report that different classes of metal ligands including 8HQ and phenanthroline derivatives and the sulfur compound PDTC (pyrrolidine dithiocarbamate) elevated cellular metal levels (copper and zinc), and resulted in substantial loss of secreted Abeta. Generally, the ability to inhibit Abeta levels correlated with a higher lipid solubility of the ligands and their capacity to increase metal uptake. However, we also identified several ligands that potently inhibited Abeta levels while only inducing minimal change to cellular metal levels. Metal ligands that inhibited Abeta levels [e.g. CQ, 8HQ, NC (neocuproine), 1,10-phenanthroline and PDTC] induced metal-dependent activation of PI3K and JNK, resulting in JNK-mediated up-regulation of metalloprotease activity and subsequent loss of secreted Abeta. The findings in the present study show that diverse metal ligands with high lipid solubility can elevate cellular metal levels resulting in metalloprotease-dependent inhibition of Abeta. Given that a structurally diverse array of ligands was assessed, the results are consistent with the effects being due to metal transport rather than the chelating ligand interacting directly with a receptor.
生物金属在阿尔茨海默病（AD）中发挥着重要作用，金属配体作为治疗AD的潜在治疗剂已被研究。在最近的研究中，8-羟基喹啉（8HQ）衍生物氯碘羟喹（CQ）在动物模型和小型临床试验中显示出了有前景的结果；然而，其体内实际作用模式仍在研究中。我们之前报道过，CQ-金属复合物在体外通过激活磷脂酰肌醇3激酶（PI3K）和c-Jun氨基末端激酶（JNK）上调基质金属蛋白酶（MMP）活性，并且MMP活性的增加导致分泌的β淀粉样蛋白（Aβ）肽降解增强。在本研究中，我们进一步研究了金属配体影响Aβ代谢的生化机制。为实现这一目标，我们在细胞培养中测量了多种金属配体对细胞金属摄取和分泌的Aβ水平的影响。我们报道，包括8HQ和菲咯啉衍生物以及硫化合物吡咯烷二硫代氨基甲酸盐（PDTC）在内的不同种类金属配体提高了细胞金属水平（铜和锌），并导致分泌的Aβ大量减少。一般来说，抑制Aβ水平的能力与配体较高的脂溶性及其增加金属摄取的能力相关。然而，我们也鉴定出了几种配体，它们能有效抑制Aβ水平，同时仅引起细胞金属水平的最小变化。抑制Aβ水平的金属配体[如CQ、8HQ、新亚铜试剂（NC）、1,10-菲咯啉和PDTC]诱导PI3K和JNK的金属依赖性激活，导致JNK介导的金属蛋白酶活性上调以及随后分泌的Aβ减少。本研究的结果表明，具有高脂溶性的多种金属配体可提高细胞金属水平，从而导致金属蛋白酶依赖性地抑制Aβ。鉴于评估了结构多样的一系列配体，结果与这些效应是由于金属转运而非螯合配体直接与受体相互作用一致。
