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


  • S.M. Lehmann
  • C. Krueger
  • B. Park
  • K. Derkow
  • K. Rosenberger
  • J. Baumgart
  • T. Trimbuch
  • G. Eom
  • M. Hinz
  • D. Kaul
  • P. Habbel
  • R. Kaelin
  • E. Franzoni
  • A. Rybak
  • D. Nguyen
  • R. Veh
  • O. Ninnemann
  • O. Peters
  • R. Nitsch
  • F.L. Heppner
  • D. Golenbock
  • E. Schott
  • H.L. Ploegh
  • F.G. Wulczyn
  • S. Lehnardt


  • Nature Neuroscience


  • Nat Neurosci 15 (6): 827-835


  • 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.