The mechanism of action of clioquinol for the treatment of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disorder, which is characterised by an increasing impairment in memory and cognitive skills that significantly hinders a person’s daily functioning. As it stands today, AD is a fatal condition that affects millions of people around the world and is expected to reach mammoth proportions by mid-century. Despite decades of research, key findings in disease aetiology and pathogenesis, discovery of new biomarkers and development of novel brain imaging compounds, AD remains incurable and an effective disease-modifying treatment is still proving to be elusive.

In parallel, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharmacotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau protein, the amyloid beta (Ab) peptide and metal ion dyshomeostasis – all of which are involved in the origin and/or progression of AD, as reviewed in Chapter 1.

This thesis aims to expand our knowledge on the mechanism of action (MOA) of one such investigational drug, clioquinol (CQ), which serves as an 8-hydroxyqionoline (8-HQ) prototype therapeutic for AD.

To this end, the interaction between CQ, metal ions and Ab was studied in vitro. Together, results in Chapter 3 and Chapter 5 demonstrate that CQ binds directly to Ab and metals (presumably by forming a ternary complex), and delivers them into neuronal cells and primary neurons, respectively. Once internalized, the ions are either retained or removed, the protein is degraded and the drug continues to recycle. This may account for the reduction in plasma and/or cerebrospinal fluid (CSF) Ab and improvement in cognitive functions observed in AD animal models and patients following intake of CQ.

During the experimental process of this dissertation (methodology detailed in Chapter 2), different neuronal cell lines were observed to be prone to cytotoxicity induced by metal-CQ complexes. Findings in Chapter 4 add to a growing literature on the anti-cancer effects of metal chelates of CQ and other compounds that, so far, have only been tested in non-neuronal cell lines and tumours.

As concluded in Chapter 6, it is hoped that this new level of understanding of CQ’s operating mode can assist in the rational development of 8-HQ derivatives and their metal complexes as medical imaging, diagnostic and/or therapeutic agents for AD and brain cancer.