Modulation of amyloid-β aggregation by histidine-coordinating cobalt(III) schiff base complexes

Marie Heffern, Pauline T. Velasco, Lauren M. Matosziuk, Joseph L. Coomes, Constantine Karras, Mark A. Ratner, William L. Klein, Amanda L. Eckermann, Thomas J. Meade

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1584-1589
Number of pages6
JournalChemBioChem
Volume15
Issue number11
DOIs
StatePublished - Jul 21 2014
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid beta
  • cobalt
  • histidine
  • oligomers

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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    Heffern, M., Velasco, P. T., Matosziuk, L. M., Coomes, J. L., Karras, C., Ratner, M. A., Klein, W. L., Eckermann, A. L., & Meade, T. J. (2014). Modulation of amyloid-β aggregation by histidine-coordinating cobalt(III) schiff base complexes. ChemBioChem, 15(11), 1584-1589. https://doi.org/10.1002/cbic.201402201