Long JM, Maloney B, Rogers JT, Lahiri DK. Novel upregulation of amyloid-β precursor protein (APP) by microRNA-346 via targeting of APP mRNA 5'-untranslated region: Implications in Alzheimer's disease. Mol Psychiatry. 2019 Mar;24(3):345-363. Epub 2018 Nov 23 PubMed.
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National Institute on Aging, National Institutes of Health
This important work characterizes a novel role of a specific microRNA (miR-346) in iron (Fe) homeostasis and Alzheimer’s disease. In elegant cellular experiments involving both immortal cells and human primary neuronal enriched cultures, as well as in human brain samples, the study demonstrates that miR-346 plays a role in the upregulation of Aβ precursor protein (APP) within the brain, and participates in maintaining APP regulation of Fe, which is disrupted in late stages of AD. This substantially extends prior studies by the same group that demonstrate how specific miRNA species (e.g., miR-153) regulate APP, and that miR-339-5p regulates BACE1 protein generation, and that both these miRNAs are dysfunctional in AD subjects (Long et al., 2014).
The AD field up to now has been primarily focused on Aβ peptide production and its misregulation by the secretases in relation to disease progression, with relatively little attention being paid to non-pathogenic functions of APP and how these can be altered by the brain microenvironment in health and disease (Nhan et al., 2015).
For example, does disruption of APP production in the normal brain contribute to neuropathogenesis? A vital physiological role for APP is metal regulation, including ferrohomeostasis. Prior research has demonstrated that Fe stimulates the generation of APP protein. This is particularly pertinent given ample evidence of Fe dyshomeostasis in AD. But what are the molecular players? How does APP regulate Fe homeostasis?
In this context, several investigators (as detailed in the article) have interrogated the regulation of APP production by Fe and shown an iron-responsive element (IRE) to be critically involved and present within the APP mRNA 5'-UTR. Other components present include an interleukin-1 (IL-1) acute box element that likely underpins the responsiveness of APP generation to neuroinflammation. Consequently, the APP mRNA 5'-UTR has been studied as an AD therapeutic target for the action of several small molecule drugs such as phenserine (Hoffer et al., 2017, and references within).
Returning to this report, Long and colleagues have discovered another important missing piece of the puzzle: the role of a novel microRNA, miR-346, operating via the same 5'UTR. That makes at least three pieces Fe, APP, miRNA346 interacting from the same platform. In short, the authors suggest a "FeAR" (Fe, APP, RNA) nexus within the APP 5'-UTR that includes an overlapping miR-346-binding site and the APP IRE. Mechanistically, 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 elevated protein production.
The discovery and characterization of such elements could provide opportunities for drug modulation to potentially target this trio through one site. To wit, a small amount of “fear” is important in maintaining societal law and order. Likewise, a well-managed amount of ”FeAR” is vital to preserve cellular law and order, in this case Fe homeostasis. Presumably, crossing a threshold would cause chaos, dysregulation and, ultimately, disease.
Long JM, Ray B, Lahiri DK. MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects. J Biol Chem. 2014 Feb 21;289(8):5184-98. Epub 2013 Dec 18 PubMed.
Nhan HS, Chiang K, Koo EH. The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol. 2015 Jan;129(1):1-19. Epub 2014 Oct 7 PubMed.
Hoffer BJ, Pick CG, Hoffer ME, Becker RE, Chiang YH, Greig NH. Repositioning drugs for traumatic brain injury - N-acetyl cysteine and Phenserine. J Biomed Sci. 2017 Sep 9;24(1):71. PubMed.
The University of Adelaide
The intense focus of the AD research community on the function of the APP gene has revealed an astonishingly complex combination of regulatory mechanisms involving transcription, mRNA stability, translation, and protein stability. Many of these mechanisms are summarized in a 2010 review by Ruberti et al. The 5'-UTR of APP mRNA includes an iron-responsive element that binds Iron Regulatory Protein 1 (IRP1) to facilitate iron homeostasis as well as an internal ribosome entry site, and an interleukin-1 acute box element to regulate APP expression under inflammatory conditions. Now Long and colleagues have shown that the microRNA miR-346 also binds in the 5'-UTR of APP mRNA in a manner that likely interferes with the binding of IRP1. Consequently, binding of miR-346 increases APP translation in opposition to the suppression of APP translation expected when cellular ferrous iron ion levels are low. This is doubly fascinating because miRNAs are usually seen to reduce expression of proteins from mRNAs rather than increasing protein expression as seen in this paper. These authors also saw that miR-346 levels were reduced in AD brain consistent with a possible role in regulation of APP expression in this pathology. Interestingly, I also note from Long and colleagues' paper that the binding site of miR-346 in the 5'-UTR of human APP is more closely conserved in the APP orthologue of the guinea pig than in the orthologues of mouse and rat. This is consistent with the apparent more rapid evolution of APP and PSEN protein-coding sequences in the mouse and rat compared to many other mammals (Sharman et al., 2013).
Ruberti F, Barbato C, Cogoni C. Post-transcriptional regulation of amyloid precursor protein by microRNAs and RNA binding proteins. Commun Integr Biol. 2010 Nov;3(6):499-503. PubMed.
Sharman MJ, Moussavi Nik SH, Chen MM, Ong D, Wijaya L, Laws SM, Taddei K, Newman M, Lardelli M, Martins RN, Verdile G. The Guinea Pig as a Model for Sporadic Alzheimer's Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes. PLoS One. 2013;8(6):e66235. PubMed.
The University of Melbourne
This is an important paper, which adds to the likelihood that APP functionally interacts with cellular iron levels. In this case, miR346 inhibits APP translation through the IRE motif at the 5'UTR. Curiously, this forecasts changes in APP levels, and therefore possibly iron metabolism, in schizophrenia. The consequences of damaged APP translation have been evidenced in the substantia nigra in Parkinson's disease, where loss of the ability of APP to promote iron efflux promotes iron-mediated toxicity (Ayton et al., 2015) possibly through ferroptosis.
Ayton S, Lei P, Hare DJ, Duce JA, George JL, Adlard PA, McLean C, Rogers JT, Cherny RA, Finkelstein DI, Bush AI. Parkinson's disease iron deposition caused by nitric oxide-induced loss of β-amyloid precursor protein. J Neurosci. 2015 Feb 25;35(8):3591-7. PubMed.
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