Citation

  • Authors: Jin M. et al.
  • Year: 2021
  • Journal: Nat Commun 12 6565
  • Applications: in vivo / siRNA / in vivo-jetPEI

Method

Before siRNA injection, siRNA was labeled with Label IT siRNA Tracker Cy5 Kit without Transfection Reagent according to the manufacturer’s procedures. Under anesthesia with 1% isoflurane, 300 ng Cy5-labeled-siRNA in 1 μl volume was injected into the retrosplenial cortex (anteroposterior, −3.0 mm form bregma; lateral, 0.6 mm; depth, 0.5 mm) of Cx3cr1-GFP mouse at 21 weeks of age using in vivo jetPEI (201-10G, Polyplus-transfection, Illkirch, France).

Abstract

Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.

Pubmed