Metal Complexing Agents for the Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal dysfunction, reactive gliosis, and the formation of amyloid plaques and neurofibrillary tangles in the brain. There is a growing body of evidence to support a central role for biometals such as copper (Cu), zinc (Zn) and iron (Fe) in many critical aspects of AD and other neurodegenerative diseases. The amyloid beta (Aβ) peptide and its parental molecule, the amyloid precursor protein (APP) both modulate homeostasis of Cu and Zn in the brain. Perturbations to biometal metabolism in AD lead to fundamental changes in Aβ and APP expression as well as peptide aggregation and free radical production. These changes can subsequently promote neuronal oxidative stress and cell toxicity. Modulation of metal bioavailability in the brain has been proposed as a potential therapeutic strategy for treatment of AD patients. The lipid soluble metal ligand, clioquinol (CQ) has shown promising results in animal models and small clinical trials involving AD patients and a new generation of metal-ligand based therapeutics is currently under development. Further research will be necessary to fully understand the complex and interdependent pathways of biometal homeostasis and amyloid metabolism in AD. This information will be critical for developing efficacious metal-based pharmaceuticals for treatment of AD while limiting side-effects from disruption of normal metal-dependent metabolic activities.