Physiological and pathological aspects of Abeta in iron homeostasis via 5'UTR in the APP mRNA and the therapeutic use of iron-chelators.
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.
Avramovich-Tirosh
Yael
Y
Department of Pharmacology, Eve Topf and USA NPF Centers of Excellence, Technion-Faculty of Medicine, Haifa, Israel. Yaelomer@yahoo.com
Amit
Tamar
T
Bar-Am
Orit
O
Weinreb
Orly
O
Youdim
Moussa B H
MB
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
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D007501:Iron