Effects of cyclen and cyclam on zinc(II)- and copper(II)-induced amyloid beta-peptide aggregation and neurotoxicity.
The aggregation of amyloid beta-peptide (Abeta) in plaques in brain tissue is highly associated with Alzheimer's disease (AD). Aberrant homeostasis of cerebral metals such as Zn(2+) and Cu(2+) may facilitate the formation of the pathogenetic amyloid plaques. Further, the accumulation of redox-active Cu(2+) in these plaques leads to the generation of reactive oxygen species, which mediates the conspicuous oxidative damage to the brain in AD. In this study, the effect of macrocyclic polyamine chelators, cyclen and cyclam, on the aggregation of Abeta40 induced by Zn(2+) or Cu(2+) was investigated using turbidometry, thioflavin T fluorescence spectroscopy, electrospray ionization mass spectrometry, inductively coupled plasma mass spectrometry, BCA protein assay, circular dichroism spectroscopy, and atomic force microscopy. The solubility of Zn(2+)- or Cu(2+)-induced Abeta40 aggregates is greatly increased by cyclen or cyclam as compared to that without chelators, and the solubilization is not affected by other essential metal ions such as Ca(2+) and Mg(2+). Moreover, the metal-induced beta-sheet structure of Abeta40 can be reconverted to its original random coil conformation, and the generation of H(2)O(2) mediated by the Cu-Abeta40 complex can also be inhibited by these chelators. Preliminary tests on neuronal cells indicate that these chelators are capable of reducing the toxicity of metal-Abeta40 aggregates. These observations suggest that cyclen and cyclam could be lead compounds as neuroprotective or neurorescue agents for the treatment of AD.
Chen
Tingting
T
State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China.
Wang
Xiaoyong
X
He
Yafeng
Y
Zhang
Changli
C
Wu
Ziyi
Z
Liao
Kuo
K
Wang
Jianjun
J
Guo
Zijian
Z
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001812:Blood-Brain Barrier; D002614:Chelating Agents / Q000737:chemistry; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000633:toxicity; D000080027:Cyclams; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D018625:Microscopy, Atomic Force; D009420:Nervous System / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000737:chemistry; D012995:Solubility; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization; D015032:Zinc / Q000737:chemistry* / Q000633:toxicity
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D000080027:Cyclams; D006571:Heterocyclic Compounds; D017382:Reactive Oxygen Species; C024560:cyclam; D003300:Copper; C038072:cyclen; D015032:Zinc