title: The effect of Cu(2+) and Zn(2+) on the Aβ42 peptide aggregation and cellular toxicity.
abstract: The coordination chemistry of Cu and Zn metal ions with the amyloid β (Aβ) peptides has attracted a lot of attention in recent years due to its implications in Alzheimer's disease. A number of reports indicate that Cu and Zn have profound effects on Aβ aggregation. However, the impact of these metal ions on Aβ oligomerization and fibrillization is still not well understood, especially for the more rapidly aggregating and more neurotoxic Aβ42 peptide. Here we report the effect of Cu(2+) and Zn(2+) on Aβ42 oligomerization and aggregation using a series of methods such as Thioflavin T (ThT) fluorescence, native gel and Western blotting, transmission electron microscopy (TEM), and cellular toxicity studies. Our studies suggest that both Cu(2+) and Zn(2+) ions inhibit Aβ42 fibrillization. While presence of Cu(2+) stabilizes Aβ42 oligomers, Zn(2+) leads to formation of amorphous, non-fibrillar aggregates. The effects of temperature, buffer, and metal ion concentration and stoichiometry were also studied. Interestingly, while Cu(2+) increases the Aβ42-induced cell toxicity, Zn(2+) causes a significant decrease in Aβ42 neurotoxicity. While previous reports have indicated that Cu(2+) can disrupt β-sheets and lead to non-fibrillar Aβ aggregates, the neurotoxic consequences were not investigated in detail. The data presented herein including cellular toxicity studies strongly suggest that Cu(2+) increases the neurotoxicity of Aβ42 due to stabilization of soluble Aβ42 oligomers.
authors.affiliation: Department of Chemistry, Washington University, One Brookings Drive, St. Louis, Missouri 63130-4899, USA. mirica@wustl.edu.
authors.forename: Anuj K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Pavlova
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Kim
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.forename: Liviu M
authors.initials: LM
authors.lastname: Mirica
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry* / Q000633:toxicity*; D005453:Fluorescence; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D013844:Thiazoles / Q000737:chemistry; D015032:Zinc / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T; D003300:Copper; D015032:Zinc