Zn2+-Aβ40 Complexes Form Metastable Quasi-spherical Oligomers That Are Cytotoxic to Cultured Hippocampal Neurons

The roles of metal ions in promoting amyloid beta-protein (A beta) oligomerization associated with Alzheimer disease are increasingly recognized. However, the detailed structures dictating toxicity remain elusive for A beta oligomers stabilized by metal ions. Here, we show that small Zn2+-bound A beta 1-40 (Zn2+-A beta 40) oligomers formed in cell culture medium exhibit quasispherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients. These quasi-spherical Zn2+-A beta 40 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 Zn2+-A beta 40 oligomers are rich in beta-sheet and cross-beta structures. Thus, Zn2+ promotes A beta 40 neurotoxicity by structural organization mechanisms mediated by coordination chemistry.