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Distinct Effects of Zn2+, Cu2+, Fe3+, and Al3+ on Amyloid-β Stability, Oligomerization, and Aggregation: AMYLOID-β DESTABILIZATION PROMOTES ANNULAR PROTOFIBRIL FORMATION*

By Wei-Ting Chen, Yi-Hung Liao, Hui-Ming Yu, Irene H. Cheng and Yun-Ru Chen


Abnormally high concentrations of Zn2+, Cu2+, and Fe3+ are present along with amyloid-β (Aβ) in the senile plaques in Alzheimer disease, where Al3+ is also detected. Aβ aggregation is the key pathogenic event in Alzheimer disease, where Aβ oligomers are the major culprits. The fundamental mechanism of these metal ions on Aβ remains elusive. Here, we employ 4,4′-Bis(1-anilinonaphthalene 8-sulfonate) and tyrosine fluorescence, CD, stopped flow fluorescence, guanidine hydrochloride denaturation, and photo-induced cross-linking to elucidate the effect of Zn2+, Cu2+, Fe3+, and Al3+ on Aβ at the early stage of the aggregation. Furthermore, thioflavin T assay, dot blotting, and transmission electron microscopy are utilized to examine Aβ aggregation. Our results show that Al3+ and Zn2+, but not Cu2+ and Fe3+, induce larger hydrophobic exposures of Aβ conformation, resulting in its significant destabilization at the early stage. The metal ion binding induces Aβ conformational changes with micromolar binding affinities and millisecond binding kinetics. Cu2+ and Zn2+ induce similar assembly of transiently appearing Aβ oligomers at the early state. During the aggregation, we found that Zn2+ exclusively promotes the annular protofibril formation without undergoing a nucleation process, whereas Cu2+ and Fe3+ inhibit fibril formation by prolonging the nucleation phases. Al3+ also inhibits fibril formation; however, the annular oligomers co-exist in the aggregation pathway. In conclusion, Zn2+, Cu2+, Fe3+, and Al3+ adopt distinct folding and aggregation mechanisms to affect Aβ, where Aβ destabilization promotes annular protofibril formation. Our study facilitates the understanding of annular Aβ oligomer formation upon metal ion binding

Topics: Protein Structure and Folding
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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