Metal complexing agents as therapies for Alzheimer’s disease

Modern research approaches into drug development for Alzheimer’s disease (AD) target β-amyloid (Aβ) accumulation in the brain. The main approaches attempt to prevent Aβ production (secretase inhibitors) or to clear Aβ (vaccine). However, there is now compelling evidence that Aβ does not spontaneously aggregate, but that there is an age-dependent reaction with excess brain metal (copper, iron and zinc), which induces the protein to precipitate into metal-enriched masses (plaques). The abnormal combination of Aβ with Cu or Fe induces the production of hydrogen peroxide, which may mediate the conspicuous oxidative damage to the brain in AD. We have developed metal-binding compounds that inhibit the in vitro generation of hydrogen peroxide by Aβ, as well as reverse the aggregation of the peptide in vitro and from human brain post-mortem specimens. Most recently, one of the compounds, clioquinol (CQ; a USP antibiotic) was given orally for 9 weeks to amyloid-bearing transgenic mice, and succeeded in markedly inhibiting Aβ accumulation. On the basis of these results, CQ is being tested in clinical trials.