THE AMYLOID cascade hypothesis states that the dementia of Alzheimer disease (AD) is caused in part by the toxic accumulation of β-amyloid (Aβ) in extracellular amyloid-containing neuritic plaques and as accumulations of neuronal cytoplasmic Aβ oligomers.1 On the basis of this hypothesis, blocking the formation of Aβ from the amyloid precursor protein by inhibiting the enzymes β-secretase and γ-secretase has been a therapeutic strategy.1 Immunization with Aβ, which effectively removed Aβ or prevented the development of Aβ plaque formation in transgenic mice carrying the human V717 F transgene, has been another clinical therapeutic approach. Vaccination with Aβ in patients resulted in clinical meningoencephalitis, so clinical trials had to be suspended.2 Innovative alternative strategies for reducing Aβ synthesis and accumulation are needed; in this issue of the ARCHIVES, Ritchie and colleagues3 present a novel strategy for reducing Aβ neurotoxcitity by attenuation of Aβ–metal ion interactions. As they point out in their article, Aβ accumulation and toxicity are influenced by zinc and copper ions.4,5 The authors posit that these metals are enriched in Aβ deposits and their removal results in the solubilization of Aβ.6 Cherny et al7 reported that the antibiotic clioquinol, which is a copper-zinc chelator, increases the solubilization of Aβ in the AD plaque from postmortem human brain tissue, reduces hydrogen peroxide generation from Aβ, and results in a significant decrease in brain Aβ deposition in a transgenic mouse model of AD.
Rosenberg RN. Metal Chelation Therapy for Alzheimer Disease. Arch Neurol. 2003;60(12):1678-1679. doi:10.1001/archneur.60.12.1678