Fig. 8. Hypothetical model of microglia NF- κB drives tau seeding/spreading and toxicity.

a In an acute model of young PS19 mouse, microglia process the inoculated exogenous tau and release seedable tau to drive tau spreading in a month. Microglial NF-κB activation accelerates the spread of tau inclusions seeded by the inoculation of exogenous tau seeds, likely due to increased tau secretion and impaired autophagy, which is rescued by NF-κB inhibition. b In the non-seeded PS19 model, tau aggregation in aged neurons is determined by tau proteostasis of neurons expressing human mutant tau transgene. Microglial NF-κB activation drives while deletion rescues tau toxicities. NF-κB activity drives down intraneuronal inclusions via unknown mechanisms, likely via stimulating tau release and/or proteolytic cleavage in these neurons.