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An unconventional role for miRNA: let-7 activates toll-like receptor 7 and causes neurodegeneration

Lehmann, Sabrina M, Krüger, Christina, Park, Boyoun, Derkow, Katja, Rosenberger, Karen, Baumgart, Jan, Trimbuch, Thorsten, Eom, Gina +17 more·2012·Nature Neuroscience
DOI 10.1038/nn.3113
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Abstract

Activation of innate immune receptors by host-derived factors exacerbates CNS damage, but the identity of these factors remains elusive. We uncovered an unconventional role for the microRNA let-7, a highly abundant regulator of gene expression in the CNS, in which extracellular let-7 activates the RNA-sensing Toll-like receptor (TLR) 7 and induces neurodegeneration through neuronal TLR7. Cerebrospinal fluid (CSF) from individuals with Alzheimer’s disease contains increased amounts of let-7b, and extracellular introduction of let-7b into the CSF of wild-type mice by intrathecal injection resulted in neurodegeneration. Mice lacking TLR7 were resistant to this neurodegenerative effect, but this susceptibility to let-7 was restored in neurons transfected with TLR7 by intrauterine electroporation of Tlr7(−/−) fetuses. Our results suggest that microRNAs can function as signaling molecules and identify TLR7 as an essential element in a pathway that contributes to the spread of CNS damage.

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Crossref · 10.1038/nn.3113

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8 of 8 references verified0 citation errors · 0 not checkable

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  • Let-7b, enriched in CSF of AD patients, activates neuronal TLR7 and triggers neurotoxic inflammation.

    “Let-7b, enriched in CSF of AD patients, activates neuronal TLR7 and triggers neurotoxic inflammation (Lehmann et al., 2012).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Lehmann et al., 2012

  • Let-7b, elevated in CSF, acts as an endogenous TLR7 ligand, linking its fluid-level increase to direct neurotoxic signaling.

    “Let-7b, elevated in CSF, acts as an endogenous TLR7 ligand, linking its fluid-level increase to direct neurotoxic signaling (Lehmann et al., 2012).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Lehmann et al., 2012

  • Elevated levels of miR-206, miR-34a, miR-125b, and let-7b in plasma or CSF reflect trophic withdrawal, apoptosis, and innate immune activation.

    “Elevated levels of miR-206, miR-34a, miR-125b, and let-7b in plasma or CSF reflect trophic withdrawal, apoptosis, and innate immune activation, highlighting their pathogenic roles in neuronal and glial cells, though cohort replication varies (Banzhaf-Strathmann et al., 2014; Lee et al., 2012; Lehmann et al., 2012; Riancho et al., 2017; Sarkar et al., 2016; Tian et al., 2014).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Lehmann et al., 2012

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Authors
Lehmann, S. M., Krüger, C., Park, B., Derkow, K., Rosenberger, K., Baumgart, J., Trimbuch, T., Eom, G., Hinz, M., Kaul, D., Habbel, P., Kälin, R., Franzoni, E., Rybak, A., Nguyen, D., Veh, R., Ninnemann, O., Peters, O., Nitsch, R., Heppner, F. L., Golenbock, D., Schott, E., Ploegh, H. L., Wulczyn, F. G., & Lehnardt, S.
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2012-05-20
Volume
15
Issue
6
Pages
827-835
ISSN
  • 1097-6256
  • 1546-1726
DOI
10.1038/nn.3113
Cited by
697
References
8
Language
en
Licence
www.springer.com/tdm (tdm)

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