Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 24, Pages 20555-20564Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.344036
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Funding
- National Institutes of Health [AG027818, CA098799]
- United States-Israel Binational Science Foundation [2007187]
- Weizmann Institute
- Israel Science Foundation
- Kimmelman Center at the Weizmann Institute
- Ambach family fund
- Human Frontier Science Program cross-disciplinary fellowship
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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.
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