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Elucidating Structural Motifs in β-Amyloid Peptide with Sub-molecular Resolution via Scanning Tunneling Microscopy


β-Amyloid aggregates in the brain play critical roles in Alzheimer’s disease, a chronic neurodegenerative condition. Amyloid-associated metal ions, particularly zinc and copper ions, have been implicated in disease pathogenesis. Despite the importance of such ions, the binding sites on the β-amyloid peptide remain poorly understood. Due to the conformational flexibility of the peptide, conventional techniques such as X-ray crystallography are not able to determine the important nonperiodic structures of this system. This work addresses these structural resolution issues of this non-crystalline biomolecule, as well as its interactions with metal ions via scanning tunneling microscopy (STM), spectroscopic imaging, and image segmentation tools.

Our findings reveal critical interactions of an initially disordered region of β-amyloid (Aβ1-16) with copper and zinc ions. Based on our analyses of the STM images, we elucidate and outline similarities and differences between Cu2+ and Zn2+ interactions with Aβ1-16 with sub molecular resolution. We show that both metal ions participate in inter-strand Aβ1-16 binding by coordinating with the two histidine residues at positions 13 and 14 (His13 and His14) on adjacent strands and not intra-strand binding, as it had been hypothesized previously.

We found that the non-periodic binding of both types of metal ions results in more ordered peptide assemblies, but pristine β-sheets are formed only in the presence of copper. These results indicate that the bound copper has strong, long-range stabilizing effects on the assembly, whereas zinc ions are associated with local destabilizing effects. We also identified several amino acids within the peptide, which are more strongly influenced by metal ion binding, suggesting possible targets for pharmacological intervention.

Finally, we address the interactions of the remaining β-amyloid fragment, containing the last 26 residues of the full length β-amyloid peptide (p3 or Aβ17-42), with copper ions. Because it is generated in the non-amyloidogenic pathway, Aβ17-42 has been considered a non-pathogenic peptide, and, until now, its function and its role remain undetermined. Recent reports suggest that the segment may be involved in Alzheimer’s disease and Down syndrome. However, the production of Aβ17-42 as well as its dependence and involvement in metal ion misbalance have not been well studied. Thus, herein, we address structural changes in Aβ17-42 due to its interaction with Cu2+ ions. Our results based on techniques such as cyclic voltammetry indicate interaction between Cu2+ ions and Aβ17-42; furthermore, results based on surface-enhanced Raman spectroscopy, atomic force microscopy, and scanning tunneling microscopy suggest that the interaction between Cu2+ ions and Aβ17-42 ultimately leads to changes in Aβ17-42 secondary structure, shifting it from less to more β-sheet content, and its aggregation state, shifting it from a less aggregated to a more aggregated state.

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