title: The metallobiology of Alzheimer's disease.
abstract: The cause of Alzheimer's disease (AD) is closely related to the aggregation of a normal protein, beta-amyloid (Abeta), within the neocortex. Recently, evidence has been gathered to suggest that Abeta precipitation and toxicity in AD are caused by abnormal interactions with neocortical metal ions, especially Zn, Cu and Fe. However, Abeta might also participate in normal metal-ion homeostasis. An inevitable, age-dependent rise in brain Cu and Fe might hypermetallate the Abeta peptide, causing the catalysis of H(2)O(2) production that mediates the toxicity and auto-oxidation of Abeta. The greater incidence of AD in females could be due to greater constitutive activity of the synaptic Zn transporter ZnT3, and attenuated binding of metal ions to the rodent homologue of Abeta might explain why these animals are spared Alzheimer's pathology. Compounds that interdict metal-ion binding to Abeta dissolve brain deposits in vitro and one such compound, clioquinol, inhibits Abeta deposition in the Tg2576 mouse model for AD and could be useful clinically. These insights could also apply to other degenerative disorders in which metal-ion-protein interactions have been implicated.
authors.affiliation: Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, Building 114, 16th Street, Charlestown, MA 02129, USA. bush@helix.mgh.harvard.edu
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D000563:Amebicides / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D007464:Clioquinol / Q000627:therapeutic use; D006801:Humans; D008670:Metals / Q000378:metabolism* / Q000633:toxicity; D019579:Neocortex / Q000378:metabolism / Q000473:pathology
chemical_list: D000563:Amebicides; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008670:Metals; D007464:Clioquinol