{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:41:19Z","timestamp":1789072879722,"version":"build-2803163510"},"reference-count":138,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018990","name":"Alfaisal University","doi-asserted-by":"publisher","award":["IRG25444"],"award-info":[{"award-number":["IRG25444"]}],"id":[{"id":"10.13039\/501100018990","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Iron accumulation in the brain is widespread in Alzheimer\u2019s disease (AD), the most common cause of dementia. According to numerous studies, too much iron triggers the development of neurofibrillary tangles (NFTs) and amyloid-\u03b2 (A\u03b2) plaques, both of which accelerate the onset of AD. Iron sequestration and storage were disrupted by high iron, and the pattern of interaction between iron regulatory proteins (IRPs) and iron-responsive elements (IREs) was altered. The 5\u2032-untranslated regions (5\u2032-UTRs) of their APP mRNA transcripts have an IRE stem-loop, which is where iron influx enhances the translation of the amyloid precursor protein (APP). Iron regulated APP expression via the release of the repressor interaction of APP mRNA with IRP1 by a pathway similar to the iron control translation of the ferritin mRNA by the IREs in their 5\u2032-UTRs. This leads to an uncontrolled buildup of redox active Fe2+, which exacerbates neurotoxic oxidative stress and neuronal death. Fe2+ overload upregulates the APP expression and increases the cleavage of APP and the accumulation of A\u03b2 in the brain. The level of APP and A\u03b2, and protein aggregates, can be downregulated by IRPs, but are upregulated in the presence of iron overload. Therefore, the inhibition of the IRE-modulated expression of APP or Fe2+ chelation offers therapeutic significance to AD. In this article, I discuss the structural and functional features of IRE in the 5\u2032-UTR of APP mRNA in relation to the cellular Fe2+ level, and the link between iron and AD through the amyloid translational mechanism. Although there are currently no treatments for AD, a progressive neurodegenerative disease, there are a number of promising RNA inhibitor and Fe2+ chelating agent therapeutic candidates that have been discovered and are being validated in April 2025 clinical trials. Future studies are expected to further show the therapeutic efficacy of iron-chelating medications, which target the APP 5\u2032-UTR and have the ability to lower APP translation and, consequently, A\u03b2 levels. As a result, these molecules have a great deal of promise for the development of small-molecule RNA inhibitors for the treatment of AD.<\/jats:p>","DOI":"10.3390\/ijms26115283","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T11:40:32Z","timestamp":1748864432000},"page":"5283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Iron-Mediated Overexpression of Amyloid Precursor Protein via Iron Responsive mRNA in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2300-4595","authenticated-orcid":false,"given":"Mateen A.","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Life Science, College of Science and General Studies, Alfaisal University, Riyadh 11533, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/nrn.2017.29","article-title":"Not just amyloid: Physiological functions of the amyloid precursor protein family","volume":"18","author":"Deller","year":"2017","journal-title":"Nat. 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