Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of the hallmarks of the disease is the presence of both soluble and insoluble aggregates of the amyloid beta (Aβ) peptide in the brain, and these aggregates are considered central to disease progression. Thus, the development of small molecules capable of modulating Aβ peptide aggregation may provide critical insight into the pathophysiology of AD. In this work we investigate how photoactivation of three distorted Ru(ii) polypyridyl complexes (Ru1–3) alters the aggregation profile of the Aβ peptide. Photoactivation of Ru1–3 results in the loss of a 6,6′-dimethyl-2,2′-bipyridyl (6,6′-dmb) ligand, affording cis-exchangeable coordination sites for binding to the Aβ peptide. Both Ru1 and Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline ligand, as compared to a 2,2′-bipyridine ligand for Ru3, and we show that the presence of the phenanthroline ligand promotes covalent binding to Aβ peptide His residues, and in addition, leads to a pronounced effect on peptide aggregation immediately after photoactivation. Interestingly, all three complexes resulted in a similar aggregate size distribution at 24 h, forming insoluble amorphous aggregates as compared to significant fibril formation for peptide alone. Photoactivation of Ru1–3 in the presence of pre-formed Aβ1–42 fibrils results in a change to amorphous aggregate morphology, with Ru1 and Ru2 forming large amorphous aggregates immediately after activation. Our results show that photoactivation of Ru1–3 in the presence of either monomeric or fibrillar Aβ1–42 results in the formation of large amorphous aggregates as a common endpoint, with Ru complexes incorporating the extended phenanthroline ligand accelerating this process and thereby limiting the formation of oligomeric species in the initial stages of the aggregation process that are reported to show considerable toxicity.
Highlights
Alzheimer's disease (AD) is the most common form of dementia and is currently the 5th leading cause of death worldwide
This study demonstrates the ability of photoactivated Ru1–3 to target and modulate the aggregation pathway of the amyloid beta (Ab) peptide. 1H NMR showed release of the 6,60-dmb ligand and His residue shi s for Ru1 and Ru2, indicating that these residues are involved in the binding process
Electronic supplementary information (ESI)-MS con rmed the release of the 6,60-dmb ligand upon photoactivation, and showed the presence of complex–peptide adducts for Ru1–3
Summary
Alzheimer's disease (AD) is the most common form of dementia and is currently the 5th leading cause of death worldwide. An up eld shi of the His residue at 7.78 ppm is observed for Ru2 upon photoactivation in the presence of Ab1–16 (Fig. S7†), and our results are consistent with metal complex – Ab binding reported for Ru(III) complexes,[68] and for Pt(II) complexes reported by Guo et al.[69] and Hureau et al.,[29] indicating that the His residues are involved in the interaction of Ru1–2 with Ab. 7512 | Chem.
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