Modulation of Amyloid-β Aggregation by Histidine-Coordinating Cobalt(III) Schiff Base Complexes
Oligomers of the A beta 42 peptide are significant neurotoxins linked to Alzheimer's disease (AD). Histidine (His) residues present at the N terminus of A beta 42 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 A beta toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co-sb) were evaluated for their ability to interact with A beta peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co-sb complexes could interact with the His residues in a truncated A beta 16 peptide representing the A beta 42 N terminus. Coordination of Co-sb complexes altered the structure of A beta 42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of A beta correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co-sb complexes in anti-AD therapeutic approaches.
Heffern, Marie C., Pauline T. Velasco, Lauren M. Matosziuk, Joseph L. Coomes, Constantine Karras, Mark A. Ratner, William L. Klein, Amanda L. Eckermann, and Thomas J. Meade. “Modulation of Amyloid-Β Aggregation by Histidine-Coordinating Cobalt(III) Schiff Base Complexes.” ChemBioChem 15, no. 11 (2014): 1584–89. doi:10.1002/cbic.201402201.