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APP\u2019s non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~\u200920 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3\u2032-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5\u2032-UTR to upregulate APP translation and A\u03b2 production. This upregulation is reduced but not eliminated by knockdown of argonaute 2. The target site for miR-346 overlaps with active sites for an iron-responsive element (IRE) and an interleukin-1 (IL-1) acute box element. IREs interact with iron response protein1 (IRP1), an iron-dependent translational repressor. In primary human brain cultures, miR-346 activity required chelation of Fe. In addition, miR-346 levels are altered in late-Braak stage AD. Thus, miR-346 plays a role in upregulation of APP in the CNS and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. Further work will be necessary to integrate other metals, and IL-1 into the Fe-miR-346 activity network. We, thus, propose a \u201cFeAR\u201d (Fe, APP, RNA) nexus in the APP 5\u2032-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a \u201chealthy FeAR\u201d exists, activities of miR-346 and IRP\/Fe interact to maintain APP homeostasis. Disruption of an element that targets the FeAR nexus would lead to pathogenic disruption of APP translation and protein production.<\/jats:p>","DOI":"10.1038\/s41380-018-0266-3","type":"journal-article","created":{"date-parts":[[2018,11,23]],"date-time":"2018-11-23T15:48:29Z","timestamp":1542988109000},"page":"345-363","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":134,"title":["Novel upregulation of amyloid-\u03b2 precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5\u2032-untranslated region: Implications in Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0769-604X","authenticated-orcid":false,"given":"Justin M.","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-9649","authenticated-orcid":false,"given":"Bryan","family":"Maloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack T.","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-5933","authenticated-orcid":false,"given":"Debomoy K.","family":"Lahiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,11,23]]},"reference":[{"key":"266_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/NEN.0b013e3181919a48","volume":"68","author":"PT Nelson","year":"2009","unstructured":"Nelson PT, Braak H, Markesbery WR. 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