title: Metallostasis in Alzheimer's disease.
abstract: 2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia.
authors.forename: Peng
authors.initials: P
authors.lastname: Lei
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: ashleyib@unimelb.edu.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D003300:Copper / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism; D018384:Oxidative Stress; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D003300:Copper; D007501:Iron; D015032:Zinc
keywords: Alzheimer's disease; Amyloid; Copper; Free radicals; Iron; Tau; Zinc