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Regional and temporal miRNAs expression profile in a transgenic mouse model of tauopathy: implication for its pathogenesis

Molecular Psychiatry volume 26, pages 7020–7028 (2021)Cite this article

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Abstract

Studies have shown that the expression level of different microRNAs (miRNAs) is altered in neurodegenerative disorders including tauopathies, a group of diseases pathologically defined by accumulation of tau protein in neurons and glia cells. However, despite this evidence we still do not know whether miRNA changes precede their onset, thus potentially contributing to the pathogenesis, or are downstream events secondary to tau pathology. In the current paper, we assessed the miRNA expression profile at different age time points and brain regions in a relevant mouse model of human tauopathy, the hTau mice, in relationship with the development of behavioral deficits and tau neuropathology. Compared with age-matched control, four specific miRNAs (miR-132-3p, miIR-146a-5p, miR-22-3p, and miR-455-5p) were found significantly upregulated in 12-month-old hTau mice. Interestingly, three of them (miR-132-3p, miR-146a-5p, and miR-22-3p) were already increased in 6-month-old mice, an age before the development of tau pathologic phenotype. Investigation of their predicted targets highlighted pathways relevant to neuronal survival and synaptic function. Collectively, our findings support the new hypothesis that in tauopathies the change in the expression level of specific miRNAs is an early event and plays a functional role in the pathogenesis of the diseases by impacting several mechanisms involved in the development of the associated neuropathology.

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Fig. 1: miRNAs array comparison of cortex, hippocampus, and cerebellum from hTau and wild-type control mice.
Fig. 2: Temporal and region-specific profile of differentially expressed miRNAs in hTau mice.
Fig. 3: Age-dependent miRNAs change in cortex, hippocampus, and cerebellum of hTau and WT mice.
Fig. 4: Signaling pathways associated with the dysregulated miRNAs.

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Acknowledgements

Special thanks to Dr Peter Davies for providing the MC1 antibody. Domenico Praticò is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s Research. This study was supported in part by a grant from the Pennsylvania Department of Health, PA-CURE (SAP#4100083099) to DP.

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Authors and Affiliations

  1. Alzheimer’s Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA

    Elisabetta Lauretti, Ozlem Dincer & Domenico Praticò

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  1. Elisabetta Lauretti
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  2. Ozlem Dincer
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  3. Domenico Praticò
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EL and DP designed the study. EL and OD performed the experiments. EL and DP wrote the manuscript. All the authors discussed the results and have seen the final version of the paper before submission.

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Correspondence to Domenico Praticò.

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Lauretti, E., Dincer, O. & Praticò, D. Regional and temporal miRNAs expression profile in a transgenic mouse model of tauopathy: implication for its pathogenesis. Mol Psychiatry 26, 7020–7028 (2021). https://doi.org/10.1038/s41380-020-0655-2

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