Iron influx increases the translation of the Alzheimer amyloid precursor protein (APP) via an iron-responsive element (IRE)RNA
Alzheimer disease (AD)3 is a neurodegenerative process that is the leading cause of death worldwide for people over the age of 65 (1, 2). The pathological hallmarks of AD in the brain cortex are not only abundant extracellular amyloid plaques (3) and intracellular tangles of the neurofibrillary protein tau but also increased brain iron (in ferritin-associated plaques) (4).The major component of these plaques is the 40 -42-amino acid -amyloid (A) peptide cleaved from the amyloid precursor protein (APP) (5), which is the ubiquitously expressed trans-membrane metalloprotein (6). -Secretase and ␥-secretases generate the 40 -42-amino acid A peptide that is toxic to brain neurons, an event that is accelerated in the presence of iron (7-11). Intracellular iron levels control APP translation via iron-responsive 5Ј-untranslated region (APP 5Ј-UTR) sequences in the APP transcript (1, 12), likely mediated via internal ribosome entry mechanisms (13).In mammalian cells, iron homeostasis is regulated by posttranscriptional events by iron regulatory proteins (IRP1 and IRP2) that bind at high affinity to iron-responsive element (IRE) RNA hairpins and repress the translation of the iron storage protein ferritin as well as transcripts of other iron-associated proteins (14 -16). During conditions of iron influx, both IRP1 and IRP2 are released from the light (L) and heavy (H) ferritin IREs to increase the translational efficiency of the L-and H-chains of this intracellular iron storage multimer (17,18). Transferrin receptor (TfR) mRNA stability is controlled by five IREs (19,20) in its 3Ј-UTR, which binds IRP2 more avidly than IRP1 and thereby stabilizes TfR mRNA in a low intracellular iron milieu. Emerging evidence clearly supports iron directly interacting with the L-and H-ferritin IREs to weaken equal binding of IRP1-IRP2 (21).The canonical IRE stem loops encoded by L-and H-ferritin and TfR mRNAs are highly conserved throughout evolution. Similar 5Ј-UTR-specific IREs control the translation of Hif-2␣ (22), ferroportin (IREG-1) (23), the erythroid heme biosynthetic aminolevulinate synthase (eALAS) (24), and mitochondrial aconitase (25), each of which bind avidly to IRP1 to a greater degree than IRP2. In contrast to TfR mRNA, which binds at high affinity to IRP2, the duodenal divalent metal ion transporter (DMT1) (26) encodes an IRE stem loop immediately downstream from its stop codon and preferentially binds * This work was supported, in whole or in part, by National Institutes of Health Grant AG20181 (to J. T. R.). This work was also supported by a Zenith award from the Alzheimer's Association (to J. T. R.