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Mol Psychiatry. 2018 Nov 23. doi: 10.1038/s41380-018-0266-3. [Epub ahead of print]

Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease.

Author information

1
Department of Psychiatry, Laboratory of Molecular Neurogenetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
2
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
3
Neurochemistry Laboratory, Department of Psychiatry-Neuroscience, MGH, Harvard Medical School, Charlestown, MA, 02129, USA.
4
Department of Psychiatry, Laboratory of Molecular Neurogenetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. dlahiri@iupui.edu.
5
Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. dlahiri@iupui.edu.
6
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. dlahiri@iupui.edu.
7
Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. dlahiri@iupui.edu.

Abstract

In addition to the devastating symptoms of dementia, Alzheimer's disease (AD) is characterized by accumulation of the processing products of the amyloid-β (Aβ) peptide precursor protein (APP). APP's non-pathogenic functions include regulating intracellular iron (Fe) homeostasis. MicroRNAs are small (~ 20 nucleotides) RNA species that instill specificity to the RNA-induced silencing complex (RISC). In most cases, RISC inhibits mRNA translation through the 3'-untranslated region (UTR) sequence. By contrast, we report a novel activity of miR-346: specifically, that it targets the APP mRNA 5'-UTR to upregulate APP translation and Aβ 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 "FeAR" (Fe, APP, RNA) nexus in the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. When a "healthy FeAR" 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.

PMID:
30470799
DOI:
10.1038/s41380-018-0266-3

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