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 beta-amyloid peptides (A beta) 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 A beta aggregates rather than mature A beta 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 A beta 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 A beta 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 A beta aggregation and serve as potential drugs for AD. In a recent pioneering study Barnham et al. showed that platinum(II) phenanthroline complexes strongly inhibit A beta oligomerisation and attenuate its neurotoxicity in vitro. A number of additional examples involving metal complexes as inhibitors of A beta 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. (C) 2012 Elsevier B.V. All rights reserved.