Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy

Nat Commun. 2022 Apr 12;13(1):1969. doi: 10.1038/s41467-022-29552-6.


Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity. Constitutive activation of microglial NF-κB exacerbated, while inactivation diminished, tau seeding and spreading in young PS19 mice. Inhibition of NF-κB activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Inhibition of microglial NF-κB in aged PS19 mice rescued tau-mediated learning and memory deficits, restored overall transcriptomic changes while increasing neuronal tau inclusions. Single cell RNA-seq revealed that tau-associated disease states in microglia were diminished by NF-κB inactivation and further transformed by constitutive NF-κB activation. Our study establishes a role for microglial NF-κB signaling in mediating tau spreading and toxicity in tauopathy.

MeSH terms

  • Animals
  • Mice
  • Microglia* / metabolism
  • Microglia* / pathology
  • NF-kappa B* / metabolism
  • Tauopathies* / metabolism
  • Tauopathies* / pathology
  • tau Proteins* / metabolism


  • Mapt protein, mouse
  • NF-kappa B
  • tau Proteins