Challenges associated with metal chelation therapy in Alzheimer's disease

Abstract

A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term "metal targeted strategies" seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined.

Fig. 1

Percentage of elemental charge distribution in control and AD brains. A, frontal cortex; B, hippocampus [3].

Fig. 2

Schematic representation of Aβ aggregation pathway. The Aβ monomers and the intermediate forms bind the excess metal ions (M) giving rise to higher-order structures. There is a need to understand which form of the peptide is generated by the solubilization of plaques by metal chelators. (Colours are visible in the electronic version of the article at www.iospress.nl.)

Fig. 3

Molecular structures of curcumin (I), demethoxycurcumin (II), and bisdemethoxycurcumin (III).