One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH 7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with CuII, 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ1–40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of CuII. Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ1 −42 in the presence and absence of CuII, 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of CuII. However, in the presence of ligands and CuII, the results match those for the peptide alone, suggesting that the ligands function by sequestering CuII and limiting oligomer formation in this assay.
Gomes, L. M. F., Vieira, R. P., Jones, M. R., Wang, M. C. P., Dyrager, C., Souza-Fagundes, E. M., Da Silva, J. G., Storr, T., Beraldo, H. 8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated AB peptide aggregation, J. Inorg. Biochem., 2014, 139, 106-116. DOI: 10.1016/j.jinorgbio.2014.04.011
8-Hydroxyquinoline Schiff-base Compounds as Antioxidants and Modulators of Copper-Mediated Aβ Peptide Aggregation
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Funder: Alzheimer Society of Canada
Funder: Swedish Research Council
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