Project No. 2334

PRIORITY PROJECT

Primary Supervisor

Dr George Kostakis- University of Sussex

Co-Supervisor(s)

Prof Louise Serpell – University of Sussex

Dr Arjuna Ratnayaka – University of Southampton

Summary

The generative cause of Alzheimer’s disease (AD) remains unknown.

Research evidence validates the relationship between AD and metal homeostasis dysregulation and the aggregation and deposition of amyloid-β (Aβ) and tau in the brain and the neuroretina, but understanding its genesis is still challenging. To do this, ground-breaking approaches crossing chemical and biochemical boundaries are necessary to approach this problem from different angles. Specifically, the interaction of Cu, one of the three primary transition elements (Fe, Cu and Zn) found in the human body with Aβ is a possible causative factor. However, the Cu/Aβ interaction mechanism remains unknown. Cu is a labile transition metal with different oxidation states which can participate, even catalytically, in redox reactions and understanding its behaviour, in aqueous media, in the presence of substrates is challenging. The use of small organic molecules (soms) is a sophisticated approach to explaining the interaction mechanism; soms either remove Cu from Aβ or prevent Cu redox potential. However, som design is challenging as it should be selective to Cu over Zn/Fe; metabolically stable, non-toxic, water-soluble, and pass through the blood-brain and/or the blood-retinal barriers to reach the target site.

This multidisciplinary project, led by three PIs (Kostakis/Sussex), (Serpell/Sussex) and (Ratnayaka/Southampton), builds on collaborative results1, and aims to develop a library of soms, designed explicitly targeting Cu ions to study their role in Cu/Aβ interactions (solution behaviour, complexation ability, prevent or removal of Cu) in cells models of the brain and the neuroretina.

Findings can provide new insights into the fundamental mechanisms of Ab-mediated cellular toxicity underpinning age-associated conditions such as Alzheimer’s and age-related macular degeneration. The project will build on our previous discoveries, including optimised cell assays and detection methods, thus work on the chemistry-biology interface to develop novel treatments for complex illnesses of the brain and retina.