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

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.

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

“…Another activity of APP is its contribution to Fe (iron) homeostasis in neuronal cells [100][101][102][103] . In particular, this operates through a site in the APP 5′-UTR that binds iron response protein 1 (IRP1) 100,101,103 , interleukin 1 (IL1) 102,104,105 , and microRNA-346 100 . This "FeAR (Fe, APP, RNA) nexus" may also play a feedback role in αsecretase processing of APP, given that Fe also modulates α-secretase cleavage of APP 106 , specifically to increase sAPPα cellular retention and inhibit BACE1 activity 107 .…”

MicroRNAs Modulate the Pathogenesis of Alzheimer’s Disease: An In Silico Analysis in the Human Brain

“…miR-219 is also downregulated in the same cortex, which targets the Tau protein [ 7 ], while miR-125b is upregulated, which targets DUSP6, PPP1CA, and Bcl-W [ 6 ]. The miR-346 and miR-455 are upregulated, and they both target APP [ 15 , 16 ]. In addition, miR-455 also targets NGF, and along with miR-3613, miR-4674, miR6722, THBS1, COL3A1, RUXN1, TP73, EXT1, CDKN2A, and PSME3 [ 14 , 16 ].…”

“…The miRNAs in red were found to be upregulated, while those in green are downregulated. The targets are identified in the temporal (blue) or the frontal (orange) cortex [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. The figure was drawn using the vector image bank of Servier Medical Art by Servier ( ).…”

Plasma miRNAs as Biomarkers for Amnestic Mild Cognitive Impairment and Modulation on BACE1

“…Recently, the role of altered miRNAs in the diagnosis for AD has been extensively studied. Several miRNAs have been shown to regulate AD-relative genes, such as amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1), and brain-derived neurotrophic factor (BDNF) [21][22][23] . This ability of selected miRNAs to target mRNAs which are altered in disease conditions makes them potential candidate as therapeutics or as targets of therapeutics.…”