title: Zn2+-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons.
abstract: The roles of metal ions in promoting amyloid β-protein (Aβ) oligomerization associated with Alzheimer disease are increasingly recognized. However, the detailed structures dictating toxicity remain elusive for Aβ oligomers stabilized by metal ions. Here, we show that small Zn(2+)-bound Aβ1-40 (Zn(2+)-Aβ40) oligomers formed in cell culture medium exhibit quasi-spherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients. These quasi-spherical Zn(2+)-Aβ40 oligomers irreversibly inhibit spontaneous neuronal activity and cause massive cell death in primary hippocampal neurons. Spectroscopic and x-ray diffraction structural analyses indicate that despite their non-fibrillar morphology, the metastable Zn(2+)-Aβ40 oligomers are rich in β-sheet and cross-β structures. Thus, Zn(2+) promotes Aβ40 neurotoxicity by structural organization mechanisms mediated by coordination chemistry.
authors.affiliation: Department of Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Solomonov
authors.forename: Eduard
authors.initials: E
authors.lastname: Korkotian
authors.forename: Benjamin
authors.initials: B
authors.lastname: Born
authors.forename: Yishay
authors.initials: Y
authors.lastname: Feldman
authors.forename: Arkady
authors.initials: A
authors.lastname: Bitler
authors.forename: Farid
authors.initials: F
authors.lastname: Rahimi
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017433:Protein Structure, Secondary; D051381:Rats; D014961:X-Ray Diffraction; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D015032:Zinc