. MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem. 2010 Jun 11;285(24):18344-51. PubMed.


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  1. The paper by Elisa Vilardo et al. on miR-101 regulating APP (Francesca Ruberti, corresponding author) looks like a very nice addition to the growing literature indicating that genes related to neurodegeneration in humans are regulated in part through miRNAs. This study seems thoughtfully designed, and the presentation of the phylogenetic and biochemical information is very helpful. In sum, there have now been a fair number of papers that show that APP is regulated via miRNAs through sequence elements in the 3'UTR. Like BACE1 and other genes, it appears that APP gene expression regulation entails a complex medley of transcriptional, splicing, translational, post-translational, and proteolysis regulation. Biology has no obligation to be simple!

    These studies are all the more relevant because of two features of neurodegenerative diseases such as Alzheimer disease (AD) and synucleinopathies: 1) they appear to have a prominent gene dosage effect related to APP and α-synuclein, respectively; and 2) these diseases seem to involve long-term subtle disequilibrium, such that even pathways that only subtly shift the equilibrium could (if manipulated over a long time) provide possible therapeutic targets.

    I can add that, in our hands, miR-101 seems to be moderately to highly expressed in human cerebral cortex, and its expression seems mildly decreased in AD brains (unpublished observations), which is compatible with the authors’ hypothesis that this miRNA may be contributing to APP expression and Aβ deposition.

  2. Another player is added to the list of microRNAs involved in the regulation of APP: miR-101. To my knowledge, this is the fourth group reporting the indirect (1) and direct (2-4) regulation of APP expression by microRNAs. Others include let-7 and miR-20 family members, that is, miR-20a, miR-106a, miR-106b, and miR-17-5p. It is noteworthy that synergic effects of microRNAs on mRNA target genes have been documented. This, therefore, opens the possibility that several microRNAs could regulate the expression of APP (and other AD-related genes) in vitro, and most importantly, in vivo. Interestingly, miR-101, let-7i, and miR-106b are predicted to be downregulated in AD brain (2,5,6).

    In this study, miR-101 is inversely correlated with APP in the developing rat brain and neurons, while gain- and loss-of-function paradigms demonstrate that miR-101 can regulate APP in primary neurons (a first!). On this line of thought, many researchers utilize rat (instead of mouse) primary neurons for microRNA functional assays, likely because of higher transfection efficiencies. In our hands, APP expression was too variable in mouse primary neurons, making definitive conclusions difficult (as discussed in [2]). In this study, the authors rely on lentiviruses to express microRNA mimics, or inhibitors, in neuronal cells. Unfortunately, the relative expression and inhibition of miR-101, respectively, using these constructs are not shown.

    An interesting observation is the upregulation of APP protein in Ago2 knockdown cells. This observation, per se, strongly supports the role of microRNAs in general in the physiological regulation of APP in neurons. The challenge now is to validate these findings in vivo to fully understand the contribution of microRNAs in APP physiology and pathology.


    . The expression of the Alzheimer's amyloid precursor protein-like gene is regulated by developmental timing microRNAs and their targets in Caenorhabditis elegans. Dev Biol. 2008 Mar 15;315(2):418-25. PubMed.

    . MicroRNA regulation of Alzheimer's Amyloid precursor protein expression. Neurobiol Dis. 2009 Mar;33(3):422-8. PubMed.

    . MicroRNAs can regulate human APP levels. Mol Neurodegener. 2008;3:10. PubMed.

    . MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem. 2010 Jun 11;285(24):18344-51. PubMed.

    . Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation. PLoS One. 2010;5(2):e8898. PubMed.

    . Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20. Epub 2008 Apr 23 PubMed.

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