title: Two macrocyclic polyamines as modulators of metal-mediated Aβ40 aggregation.
abstract: Dysfunctional interactions of amyloid-β (Aβ) with Zn and Cu ions are proved to be related to the etiology of Alzheimer's disease (AD). Disruption of these metal-Aβ interactions using metal chelators holds considerable promise as a therapeutic strategy to combat this incurable disease. Herein, we report that two cyclam derivatives (L1 and L2) are capable of modulating Zn(2+)/Cu(2+)-mediated Aβ40 aggregation, reactive oxygen species (ROS) production, and neurotoxicity. These chelators were found to inhibit the metal-induced Aβ40 aggregation, dissociate metal-Aβ40 aggregates and restore the metal-induced β-sheet structure of Aβ40 to its random coil conformation, as observed by BCA protein assay, thioflavin T fluorescence and circular dichroism spectroscopy. Moreover, preliminary investigation of SH-SY5Y cells indicates that L1 and L2 can diminish the neurotoxicity of metal-Aβ40 species, control metal-Aβ40-triggered ROS production and protect cells against apoptosis. These observations warrant the further investigations of L1 and L2 as potential anti-AD agents.
authors.affiliation: School of Chemistry and Chemical Engineering, Nantong University, Nantong, 226019, P. R. China. tingtingchenntu@163.com.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Yang
authors.forename: Tingting
authors.initials: T
authors.lastname: Chen
authors.forename: Shajun
authors.initials: S
authors.lastname: Zhu
authors.forename: Xuefang
authors.initials: X
authors.lastname: Gu
authors.forename: Xueping
authors.initials: X
authors.lastname: Jia
authors.forename: Yapeng
authors.initials: Y
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008670:Metals / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D011487:Protein Conformation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D006571:Heterocyclic Compounds; D008670:Metals; D010446:Peptide Fragments; D011073:Polyamines; D066329:Protein Aggregates; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C024560:cyclam; D003300:Copper; D015032:Zinc