Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors


  • P. Dembny
  • A.G. Newman
  • M. Singh
  • M. Hinz
  • M. Szczepek
  • C. Krüger
  • R. Adalbert
  • O. Dzaye
  • T. Trimbuch
  • T. Wallach
  • G. Kleinau
  • K. Derkow
  • B.C. Richard
  • C. Schipke
  • C. Scheidereit
  • H. Stachelscheid
  • D. Golenbock
  • O. Peters
  • M. Coleman
  • F.L. Heppner
  • P. Scheerer
  • V. Tarabykin
  • K. Ruprecht
  • Z. Izsvák
  • J. Mayer
  • S. Lehnardt


  • JCI Insight


  • JCI Insight 5 (7): e131093


  • Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs, such as HERV-K(HML-2), are reported to be involved in neurological disorders, little is known about their biological function. We report that RNA from an HERV-K(HML-2) envelope gene region binds to and activates human Toll-like receptor (TLR) 8, as well as murine Tlr7, expressed in neurons and microglia, thereby causing neurodegeneration. HERV-K(HML-2) RNA introduced into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimer's disease (AD), resulted in neurodegeneration and microglia accumulation. Tlr7-deficient mice were protected against neurodegenerative effects but were resensitized toward HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Transcriptome data sets of human AD brain samples revealed a distinct correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from individuals with AD compared with controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for species-specific TLRs 7/8 and imply a functional contribution of human endogenous retroviral transcripts to neurodegenerative processes, such as AD.