Alzheimer’s disease presents a growing problem worldwide due to the economic and social burden it imposes. Amyloid beta (Aβ) peptides are fragments of varying lengths derived from the amyloid precursor protein. The aggregation of the 42-residue fragment (Aβ42) into fibrils or oligomers has been implicated in the progression of Alzheimer’s disease. Inhibiting this aggregation remains an important target in the search for effective treatments of the disease.1
The aggregation of Aβ42 follows a pathway that is analogous to crystal growth, comprising of an initial primary nucleation phase which generates seeds followed by elongation of the fibrils, or secondary nucleation to generate new seeds.2 Previously reported aggregation inhibitors function by preventing primary or secondary nucleation processes, but are not able to supress aggregation in the presence of seeds.3
We have synthesised a series of perphenazine-cyclam conjugates that redirect amyloid beta to form non-toxic aggregates, reduce amyloid formation and ameliorate the associated toxicity in neuronal cells. Kinetic studies demonstrate that these conjugates interact specifically with monomeric Aβ peptide and sequester it, supressing the growth of fibrils and intermediate oligomers even in the presence of seeds.4 This is an unusual and promising mode of small molecule interaction with Aβ which we are exploring further.
In order to elucidate the mechanism behind this behaviour, a series of protein NMR experiments utilising paramagnetic relaxation enhancement (PRE) have been devised. These experiments require modified probes, derived from cyclen and chelated with a series of lanthanide ions. The synthesis of these probes will be described. The results of these experiments can direct further research into the development of more potent inhibitors, and resolve discrepancies in our understanding of the role Aβ plays in the progression of Alzheimer’s disease.