. Microglial microRNAs mediate sex-specific responses to tau pathology. Nat Neurosci. 2019 Dec 23; PubMed.

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  1. This article describes an interesting concept, where microglial microRNAs contribute to tau pathology (in neurons) in a sex-specific manner.

    Sex differences in onset and progression in Alzheimer’s disease and related tauopathy have been previously described. The observations in this paper extend on that knowledge, but the specific role of sex-specific microRNAs in neurodegenerative disorders clearly requires further investigation. It is interesting that we and others have not seen (or noted particular) sex-specific effects of neuronal microRNAs on Tau (Hébert et al.,  2010; Hébert et al., 2012; Smith et al., 2015; Santa-Maria et al., 2015). Having said this, we would like to take the opportunity to provide some scientific viewpoints that, in our opinion, could help future directions in this area of research.  

    For instance, future experiments would require larger numbers of animals and additional variables in post-array analyses (e.g., age, background). Indeed, it is perhaps not surprising that unsupervised clustering of microRNA expression profiles points to differences between males and females, as these are the only experimental variables available. One would actually expect much more X-chromosome-related microRNAs to stand out and be used as internal controls (miR-1298 is located on Chr. X but not others). In addition, is important to mention that an independent model like a human-related cellular system will strengthen these observations.

    Interestingly, the authors observe that the PS19 mouse model has similar Tau pathology (MC1 staining) in both sexes under “basal” conditions. Indeed, the differences between males and females occur only in the absence of microRNAs (Dicer enzyme). In our hands, both female and male PS19 mice behave similarly with regard to tau pathology (immunohistochemistry, western blot), behavior, and survival (Hébert el al., unpublished), consistent with the results by Kodama et al. Luckily, other AD or tauopathy mouse models have more consistent sex-related differences that can be used to further investigate this issue.

    The authors used Dicer conditional knockouts to study the effects of microRNA deficiency on Tau pathology. While Dicer mouse models were commonly used in the past, we know now that this enzyme is responsible for the production of hundreds (if not thousands) of other small regulatory RNAs in cells, including mirtrons, endogenous small hairpin RNAs, tRNA-derived small RNAs, and small nucleolar RNA-derived miRNAs (Miyoshi et al., 2010). Additional roles associated with Dicer (methylation, chromatin structure, DNA damage, splicing, etc.) cannot be excluded either. Therefore, such crude knockout experiments would benefit from using complementary mouse models lacking other enzymes involved in microRNA maturation (e.g. Drosha or Dgcr8). Better yet, modulating specific microRNAs within microglia would obviously address these concerns.

    Unfortunately, the study of Tau pathology was limited to immunohistochemistry (IHC) using anti-Tau MC1 antibodies, directed against abnormal Tau conformation. No information was provided with regard to any post-translational modification of Tau and aggregation per se. This could be easily addressed using a myriad of techniques, especially in this mouse model highly overexpressing human mutant Tau. Thus, while the observations are intriguing, the overall effects on Tau require further investigation. Of course, many other parameters need also to be investigated in future studies (e.g., mouse behavior and survival, brain and neuron integrity, inflammation).

    Importantly, the authors propose various genes and pathways potentially implicated in modulating Tau pathology. As suggested by the authors, abnormal inflammation or phagocytosis are certainly interesting possibilities, but one should not exclude other mechanisms like autophagy and/or the transport of microRNAs between cell types. The functional relationship between Tau pathology and lipoprotein lipase upregulation, an enzyme mainly expressed in endothelial cells that hydrolyzes triglycerides in lipoproteins, remains uncertain. No other genes (including potential microRNA targets) were validated in this study. It’s noteworthy that accumulating studies suggest that only one or a limited number of key microRNA target genes are responsible for a given biological response or phenotype. Clearly, functional studies are required to draw any conclusions here. Most certainly, the effects on Tau are indirect since the PS19 mice do not contain a human Tau 3'UTR required for microRNA binding and regulation.

    In sum, this important biological evidence linking sex-specific microglial microRNAs and Tau pathogenesis presented in this research article highlights the challenges, opportunities, and necessities related to the study of microRNAs in neurodegenerative diseases.

    References:

    . Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Hum Mol Genet. 2010 Oct 15;19(20):3959-69. PubMed.

    . MicroRNAs and the Regulation of Tau Metabolism. Int J Alzheimers Dis. 2012;2012:406561. PubMed.

    . miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo. Hum Mol Genet. 2015 Dec 1;24(23):6721-35. Epub 2015 Sep 11 PubMed.

    . Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau. J Clin Invest. 2015 Feb;125(2):681-6. Epub 2015 Jan 9 PubMed.

    . Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production. Mol Genet Genomics. 2010 Aug;284(2):95-103. Epub 2010 Jul 2 PubMed.

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