title: Physiological and pathological aspects of Abeta in iron homeostasis via 5'UTR in the APP mRNA and the therapeutic use of iron-chelators.
abstract: Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-beta protein (Abeta) in reducing iron-induced neurotoxicity. Thus, given that Abeta possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Abeta, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Abeta levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD.
authors.affiliation: Department of Pharmacology, Eve Topf and USA NPF Centers of Excellence, Technion-Faculty of Medicine, Haifa, Israel. Yaelomer@yahoo.com
authors.forename: Yael
authors.initials: Y
authors.lastname: Avramovich-Tirosh
authors.forename: Tamar
authors.initials: T
authors.lastname: Amit
authors.forename: Orit
authors.initials: O
authors.lastname: Bar-Am
authors.forename: Orly
authors.initials: O
authors.lastname: Weinreb
authors.forename: Moussa B H
authors.initials: MB
authors.lastname: Youdim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D007501:Iron