Metal complexing agents as therapies for Alzheimer's disease.
Modern research approaches into drug development for Alzheimer's disease (AD) target beta-amyloid (Abeta) accumulation in the brain. The main approaches attempt to prevent Abeta production (secretase inhibitors) or to clear Abeta (vaccine). However, there is now compelling evidence that Abeta 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 Abeta 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 Abeta, 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 Abeta accumulation. On the basis of these results, CQ is being tested in clinical trials.
Bush
Ashley I
AI
Oxidation Disorders Research Unit, Mental Health Research Institute of Victoria, University of Melbourne, 155 Oak Street, Parkville VIC 3052, Australia. bush@helix.mgh.harvard.edu
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy* / Q000517:prevention & control; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002614:Chelating Agents / Q000378:metabolism / Q000627:therapeutic use; D007464:Clioquinol / Q000378:metabolism / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008670:Metals / Q000378:metabolism* / Q000627:therapeutic use*; D051379:Mice; D015032:Zinc / Q000378:metabolism / Q000627:therapeutic use
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D008670:Metals; D003300:Copper; D007464:Clioquinol; D006861:Hydrogen Peroxide; D015032:Zinc