Metal compounds as inhibitors of β-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer's disease

Alzheimer's disease (AD) is a widespread neurodegenerative disease with a very high medical, social and economic burden. The etiopathogenesis of AD is still largely obscure; however, there is growing evidence that aggregation of β-amyloid peptides (Aβ) into a variety of supramolecular structures is critically involved in its insurgence and progression (the so called “amyloid cascade hypothesis”). Recent results point to oligomeric Aβ aggregates rather than mature Aβ fibrils as the major culprit for neurotoxicity; details of the inherent aggregation processes are being progressively clarified. In view of these achievements, early stages of Aβ aggregation are considered today a realistic “druggable” target for the development of new anti-AD agents. Notably, a variety of organic compounds that are able to inhibit effectively Aβ aggregation represent promising drug candidates. Metal based compounds capable of interacting with the N-terminal metal binding site of amyloid peptides might similarly contrast metal-induced Aβ aggregation and serve as potential drugs for AD. In a recent pioneering study Barnham et al. showed that platinum(II) phenanthroline complexes strongly inhibit Aβ oligomerisation and attenuate its neurotoxicity in vitro. A number of additional examples involving metal complexes as inhibitors of Aβ aggregation were reported afterward. On the ground of those results it may be proposed that metal based compounds constitute today a suitable and rich source for novel anti-AD agents. The potential and the limits of this therapeutic option are comprehensively and critically discussed as well as the perspectives for future research.

► Aggregation of β-amyloid peptides into “soluble oligomers” constitutes a realistic druggable target for AD.
► A number of late transition metal compounds – e.g. Pt and Ru – manifest high affinity for the metal binding site of Aβ peptides and drastically alter their aggregation behaviour.
► Metal binding greatly decreases neurotoxicity in vitro of Aβ peptides.
► Metal based compounds represent promising agents for an innovative therapeutic of AD.