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 (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.

Keywords: Alzheimer's disease; amyloid beta; cobalt; histidine; oligomers.

Figure 1

¹H NMR of Aβ16 (5mM) with increasing ratios of Co-acacen:Aβ16 from 0.0 – 4.0 in D₂O buffered with 100 mM phosphate buffer to pH 7.0. Spectra were acquired at on a 500 MHz spectrometer at 25 °C after 1h incubations at 37 °C. With increasing equivalents of Co-acacen, a loss of peaks corresponding to the free His CH2 protons (7.9–8.2 ppm) is observed. New peaks are observed between 6.35–6.7 ppm, indicating His-coordination to Co-acacen (Co(III)-His) in a concentration-dependent manner. A complete loss of free His peaks is observed at ≥ 2.0 eq. of Co-acacen.

Figure 2

Thermodynamic parameters of Co(III)-sb complexes coordinated to models of His6, 13, and 14. These calculations indicate the favorability of a coordination mode with the His6 and either the His13 or His14 at the axial positions of the Co(III)-sb complex. Simultaneous coordination of the His13 and His14 is the least favorable due to strain induced on the octahedral geometry (SI Figure 7).

Figure 3

SDS-PAGE Western blots of Aβ42 oligomerized in the presence of Co-acacen, Co-benacen, and the free ligands. (A) Co-acacen shifts the distribution of SDS-stable Aβ soluble oligomers to higher MW species in a concentration-dependent manner. (B) A similar effect is observed with Co-benacen but to a greater degree, possibly due to the presence of the aromatic residues. This result is confirmed by the slight stabilization of large oligomers with the free Benacen ligand. Such disruption is not observed with the free Acacen ligand.

Figure 4

SDS-PAGE (A) silver stain profiles and (B) Western blots of Aβ42 oligomerized in the presence of Co-acacen, Pt-en and Pt-phen. In a similar manner to Co-acacen, Pt-phen shifts the distribution of SDS-stable Aβ soluble oligomers to higher MW species. This is not observed with Pt(ethylenediamine)Cl₂ (Pt-en), indicating the importance of the aromatic scaffold in Aβ structural disruption. The similarity of the effect of Co-acacen on the Aβ oligomerization to Pt-phen underscores the promise of the cobalt complexes for anti-AD therapeutic approaches.

Scheme 1

(A) Amyloid β (Aβ) peptides used in these studies. Aβ16 was used a soluble peptide model to understand the interactions between Co(III)-sb complexes and the N-terminus of the Aβ peptide. Aβ42 was used to understand the effects of Co(III)-sb complexes on peptide oligomerization and synaptic binding. (B) Transition metal complexes and naming scheme used in this chapter. Co-acacen and Co-benacen are Co(III)-sb complexes that coordinate His residues through dissociative ligand exchange of the axial ammines. The behavior of Co(III)-sb on modulating Aβ was compared to Pt-phen, a Pt(II) complex previously shown to disrupt Aβ-induced neurotoxicity. (C) Proposed scheme of the modulation of Aβ activity by Co-acacen. Co-acacen is believed to coordinate to the His residues of Aβ through the two axial positions. Computational studies suggest the simultaneous coordination of His6 and either His13 or His14 as the most stable conformation. His-coordination alters the Aβ structure, disrupting oligomerization pathways and synaptic binding.