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

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 (that 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(III)-sb) were evaluated for their ability to interact with Aβ peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co(III)-sb complexes could interact with the His residues in a truncated Aβ16 peptide representing the Aβ42 N-terminus. Coordination of Co(III)-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(III)-sb complexes in anti-AD therapeutic approaches.

Modification of Aβ Peptide Aggregation via Covalent Binding of a Series of Ru(III) Complexes

“…Several metal complexes have been reported to modulate the aggregation pattern of Aβ upon binding covalently to the peptide (Collin et al, 2013;Kenche et al, 2013;Heffern et al, 2014;Jones et al, 2015;Gomes et al, 2019). For example, the binding of FIGURE 7 | Bradford assay of 60 µM Aβ 1−42 in the presence of 1 eq.…”

“…Interestingly, smaller, soluble Aβ oligomers have been more strongly linked to memory loss and progression of the disease in comparison to plaques. These species have been implicated in the initiation of the processes of oxidative stress, decreased cerebral blood flow, neuronal hyperactivity, synapse deterioration, and nerve cell death (McLean et al, 1999;Lesne et al, 2006;Watt et al, 2013;Heffern et al, 2014;Nortley et al, 2019;Zott et al, 2019).…”

“…However, their dyshomeostasis has been observed in neurodegenerative diseases, such as AD (Curtain et al, 2001;Sung et al, 2006;Brown, 2009;Kepp, 2012;Savelieff et al, 2013;Hane and Leonenko, 2014;Ward et al, 2015). A high concentration of these metal ions are present in Aβ plaques (Savelieff et al, 2013), where they are found coordinated typically to His 6,13,or14 residues, although Asp 1 , Tyr 10 , and Glu 11 have been shown to be involved in Aβ peptide metal binding (Miller et al, 2010(Miller et al, , 2012Parthasarathy et al, 2011;Hane and Leonenko, 2014;Heffern et al, 2014;Wineman-Fisher et al, 2016). This binding can modify the aggregation pattern of Aβ, disrupt normal metalloenzyme activity, and produce toxic reactive oxygen species (ROS) (Bousejra-ElGarah et al, 2011;Lakatos et al, 2012;Pithadia et al, 2012;Hane and Leonenko, 2014;Heffern et al, 2014;Leong et al, 2014;Ward et al, 2015).…”

“…A number of Pt (Barnham et al, 2008;Sasaki et al, 2012;Collin et al, 2013;Streltsov et al, 2013), Ru (Valensin et al, 2010;Messori et al, 2013;Jones et al, 2015), Co (Suh et al, 2007;Heffern et al, 2014;Derrick et al, 2017), and V (He et al, 2015) metal complexes have shown promise in interacting with the Aβ peptide and modifying its aggregation. For example, a series of Pt(II) phenanthroline complexes (Chart 1) were shown to bind to the peptide, modulating the aggregation and the neurotoxicity of Aβ (Barnham et al, 2008).…”

Inhibition of Beta-Amyloid Fibrillation by Luminescent Iridium(III) Complex Probes

“…Due to the well-defined three-dimensional structure of transition metal complexes, highly specific interactions between metal complexes and biomolecules can be obtained through modification of the steric and electronic nature of the organic ligands surrounding the metal centre. In the context of Alzheimer’s disease, metal complexes such as Pt(II) 42 43 44 45 46 47 48 , binuclear Ru(II)–Pt(II) 49 , Ru(II) 50 51 52 , Co(III) 53 and Ir(III) or Rh(III) solvato 54 complexes have been reported to inhibit the aggregation of Aβ peptide 55 56 57 . Furthermore, luminescent metal complexes such as Ru(II) 58 59 , Re(I) 60 complexes have also been used to monitor the Aβ fibrillation process 30 55 .…”