Abstract

Alzheimer's disease (AD) is the most common form of dementia, leading to loss of cognition, and eventually death. The disease is characterized by the formation of extracellular aggregates of the amyloid-beta (Aβ) peptide and neurofibrillary tangles of tau protein inside cells, and oxidative stress. In this study, we investigate a series of Ru(III) complexes (Ru-N) derived from NAMI-A in which the imidazole ligand has been substituted for pyridine derivatives, as potential therapeutics for AD. The ability of the Ru-N series to bind to Aβ was evaluated by NMR and ESI-MS, and their influence on the Aβ peptide aggregation process was investigated via electrophoresis gel/western blot, TEM, turbidity, and Bradford assays. The complexes were shown to bind covalently to the Aβ peptide, likely via a His residue. Upon binding, the complexes promote the formation of soluble high molecular weight aggregates, in comparison to peptide precipitation for peptide alone. In addition, TEM analysis supports both amorphous and fibrillar aggregate morphology for Ru-N treatments, while only large amorphous aggregates are observed for peptide alone. Overall, our results show that the Ru-N complexes modulate Aβ peptide aggregation, however, the change in the size of the pyridine ligand does not substantially alter the Aβ aggregation process.

Highlights

  • Dementias are disorders in which severe cognitive impairment occurs (Gaggelli et al, 2006; Crouch and Barnham, 2012; DeToma et al, 2012) affecting over 50 million people worldwide (Budimir, 2011; Crouch and Barnham, 2012; WHO, 2012)

  • We have previously shown that the Ru(III) complex KP1019 interferes with Thioflavin T (ThT) fluorescence analysis (Jones et al, 2015), turbidity has been shown to be a reliable alternative for the investigation of peptide aggregation in the presence of compounds that disrupt ThT fluorescence (Cook and Martí, 2012)

  • The Ru-N series contains four NAMI-A derivatives with pyridyl ligands of different sizes (Chart 1), and it was hypothesized that an enhanced interaction with the Aβ peptide would occur for the larger more hydrophobic derivatives

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Summary

Introduction

Dementias are disorders in which severe cognitive impairment occurs (Gaggelli et al, 2006; Crouch and Barnham, 2012; DeToma et al, 2012) affecting over 50 million people worldwide (Budimir, 2011; Crouch and Barnham, 2012; WHO, 2012). An increase in life expectancy is expected to lead to a sharp increase in the number of dementia cases over the 20 years (Alzheimer’s Association, 2019). Alzheimer’s disease (AD), the most common type of dementia, represents 60–70% of dementia cases (Martin Prince et al, 2015), resulting in a significant burden to healthcare systems around the globe. AD is a neurodegenerative disease where protein misfolding and aggregation combined with oxidative stress causes neuronal cell death, leading to loss of cognition and eventually death (Crouch and Barnham, 2012; Rodriguez-Rodriguez et al, 2012; Lee et al, 2014). Treatment strategies for most neurodegenerative diseases are very limited, and approved treatments for AD only ameliorate the symptoms at early to moderate stages of the disease, making this an important research area (Roberson and Mucke, 2006; Adlard et al, 2009; Citron, 2010; Finder, 2010; Selkoe, 2011; Hickey and Donnelly, 2012; Soto and Pritzkow, 2018; Savelieff et al, 2019).

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