The Medicinal Metallochemistry of Alzheimer's Disease

The brain is an organ which is at once enriched in transition metals and highly susceptible to oxidative stress. By virtue of its high affinity for copper the Alzheimer's amyloid protein (Aβ) is capable of catalytic generation of neurotoxic H2O2 while its aggregation and deposition are zinc-dependent. These properties are exaggerated by conditions present in the aging brain. Amyloid from human brain specimens can be solubilized by the application of selected Cu / Zn chelators thus demonstrating the role of metals in amyloid architecture. Similarly, the toxicity of the metal / Aβ complex is ameliorated by metal complexing agents. Clioquinol, a bioavailable Cu / Zn chelator has been successfully used to inhibit amyloid deposition in a transgenic animal model for Alzheimer's disease and is presently undergoing human efficacy trials.