Zn²⁺-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons

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 (Zn²⁺- Aβ40) oligomers formed in cell culture medium exhibit quasispherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients. These quasi-spherical Zn²⁺-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, Zn²⁺ promotes Aβ40 neurotoxicity by structural organization mechanisms mediated by coordination chemistry.