PMID- 24513321 OWN - NLM STAT- MEDLINE DCOM- 20140519 LR - 20211021 IS - 1873-2968 (Electronic) IS - 0006-2952 (Print) IS - 0006-2952 (Linking) VI - 88 IP - 4 DP - 2014 Apr 15 TI - Alzheimer's disease therapeutics targeted to the control of amyloid precursor protein translation: maintenance of brain iron homeostasis. PG - 486-94 LID - S0006-2952(14)00071-9 [pii] LID - 10.1016/j.bcp.2014.01.032 [doi] AB - The neurotoxicity of amyloid beta (Abeta), a major cleavage product of the amyloid precursor protein (APP), is enhanced by iron, as found in the amyloid plaques of Alzheimer's disease (AD) patients. By contrast, the long-known neuroprotective activity of APP is evident after alpha-secretase cleavage of the precursor to release sAPPalpha, and depends on the iron export actions of APP itself. The latter underlie its neurotrophic and protective effects in facilitating the homeostatic actions of ferroportin mediated-iron export. Thus APP-dependent iron export may alleviate oxidative stress by minimizing labile iron thus protecting neurons from iron overload during stroke and hemorrhage. Consistent with this, altered phosphorylation of iron-regulatory protein-1 (IRP1) and its signaling processes play a critical role in modulating APP translation via the 5' untranslated region (5'UTR) of its transcript. The APP 5'UTR region encodes a functional iron-responsive element (IRE) RNA stem loop that represents a potential target for modulating APP production. Targeted regulation of APP gene expression via the modulation of 5'UTR sequence function represents a novel approach for the potential treatment of AD since altering APP translation can be used to improve both the protective brain iron balance and provide anti-amyloid efficacy. Approved drugs including paroxetine and desferrioxamine and several novel compounds have been identified that suppress abnormal metal-promoted Abeta accumulation with a subset of these acting via APP 5'UTR-dependent mechanisms to modulate APP translation and cleavage to generate the non-toxic sAPPalpha. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Bandyopadhyay, Sanghamitra AU - Bandyopadhyay S AD - Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Charlestown, MA 02129, United States. FAU - Rogers, Jack T AU - Rogers JT AD - Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, Massachusetts General Hospital (East), Charlestown, MA 02129, United States. Electronic address: jrogers@partners.org. LA - eng GR - R03 NS053652/NS/NINDS NIH HHS/United States GR - R21 NS077079/NS/NINDS NIH HHS/United States GR - R01 AG021081/AG/NIA NIH HHS/United States GR - R21 NS064853/NS/NINDS NIH HHS/United States GR - R21 NS059434/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20140207 PL - England TA - Biochem Pharmacol JT - Biochemical pharmacology JID - 0101032 RN - 0 (5' Untranslated Regions) RN - 0 (Amyloid beta-Protein Precursor) RN - 0 (RNA, Messenger) RN - E1UOL152H7 (Iron) SB - IM MH - 5' Untranslated Regions MH - Alzheimer Disease/metabolism/*therapy MH - Amyloid beta-Protein Precursor/*genetics MH - Animals MH - Brain/*metabolism MH - *Homeostasis MH - Humans MH - Iron/*metabolism MH - Mice MH - Mice, Transgenic MH - *Protein Biosynthesis MH - RNA, Messenger/genetics PMC - PMC4064675 MID - NIHMS564324 OTO - NOTNLM OT - Alzheimer's disease OT - Amyloid precursor protein OT - Brain iron homeostasis EDAT- 2014/02/12 06:00 MHDA- 2014/05/20 06:00 PMCR- 2015/04/15 CRDT- 2014/02/12 06:00 PHST- 2013/11/05 00:00 [received] PHST- 2014/01/16 00:00 [revised] PHST- 2014/01/22 00:00 [accepted] PHST- 2014/02/12 06:00 [entrez] PHST- 2014/02/12 06:00 [pubmed] PHST- 2014/05/20 06:00 [medline] PHST- 2015/04/15 00:00 [pmc-release] AID - S0006-2952(14)00071-9 [pii] AID - 10.1016/j.bcp.2014.01.032 [doi] PST - ppublish SO - Biochem Pharmacol. 2014 Apr 15;88(4):486-94. doi: 10.1016/j.bcp.2014.01.032. Epub 2014 Feb 7.