Modulation of Amyloid-β Aggregation by Histidine-Coordinating Cobalt(III) Schiff Base Complexes

Authors

  • Dr. Marie C. Heffern,

    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
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  • Pauline T. Velasco,

    1. Department of Neurobiology, Northwestern University, 2205 Tech Drive Hogan 2-160, Evanston, IL 60208-3113 (USA)
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  • Dr. Lauren M. Matosziuk,

    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
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  • Joseph L. Coomes,

    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
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  • Constantine Karras,

    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
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  • Prof. Mark A. Ratner,

    1. Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
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  • Prof. William L. Klein,

    1. Department of Neurobiology, Northwestern University, 2205 Tech Drive Hogan 2-160, Evanston, IL 60208-3113 (USA)
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  • Prof. Amanda L. Eckermann,

    Corresponding author
    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
    2. currently at Department of Chemistry, Hope College, 35 E. 12th Street, Holland, MI 49422-9000 (USA)
    • Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)===

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  • Prof. Thomas J. Meade

    Corresponding author
    1. Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)
    • Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113 (USA)===

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Abstract

Oligomers of the Aβ42 peptide are significant neurotoxins linked to Alzheimer's disease (AD). Histidine (His) residues present at the N terminus of Aβ42 are believed to influence toxicity by either serving as metal–ion binding sites (which promote oligomerization and oxidative damage) or facilitating synaptic binding. Transition metal complexes that bind to these residues and modulate Aβ toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co–sb) were evaluated for their ability to interact with Aβ peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co–sb complexes could interact with the His residues in a truncated Aβ16 peptide representing the Aβ42 N terminus. Coordination of Co–sb complexes altered the structure of Aβ42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of Aβ correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co–sb complexes in anti-AD therapeutic approaches.

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