Probing Amyloid-beta Aggregation Using Paramagnetic Complexes

Abstract

Alzheimer’s disease is the leading cause of dementia and is creating a growing economic and social burden on the aging global population. The drugs approved for the treatment of Alzheimer’s disease are only able to slow the onset of the disease. Attempts to develop treatments which halt, or reverse, cognitive decline have proven unsuccessful.

Amyloid-β is a neuronally-derived peptide which has been implicated in Alzheimer’s disease for over three decades. Amyloid-β aggregates to form fibrils which eventually deposit as amyloid plaques in the brain and has remained a popular target for the treatment of Alzheimer’s disease. Treatments that inhibit the production of amyloid-β, or remove the end-stage aggregates have not been able to ameliorate the symptoms of the disease. The demonstrated toxicity of intermediate oligomers of amyloid-β has caused research to shift towards understanding and disrupting the aggregation process itself.

This thesis focuses on the synthesis of bis-perphenazine cyclam conjugates and their complexes, which were identified in a screen of compounds that inhibit the aggregation of amyloid-β. Chapter 2 describes the development of a scalable synthesis of these compounds and further characterises their biological activity. It was found that these compounds inhibited aggregation by interacting with monomeric Aβ and that they could reduce the toxicity of Aβ towards cultured neuronal cells.

Chapters 3 and 4 describe the development of a series of probe compounds which can act as paramagnetic NMR probes to investigate how the compounds bind to amyloid-β. Attempts at synthesising bis-perphenazine lanthanide probes are described in Chapter 3. Chapter 4 describes the synthesis of a series of lanthanide probes containing one perphenazine pendant. The compounds were shown to disrupt the aggregation of Aβ in vitro but attempts to identify how the probes interacted with monomeric Aβ using paramagnetic relaxation enhancement were unsuccessful.