Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy [bulk RNA-Seq]

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-B activation enhanced the retention while reduced the release of internalized pathogenic tau fibrils from primary microglia and rescued microglial autophagy deficits. Remarkably, 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-B inactivation and further transformed by constitutive NF-B activation. Our study establishes a central role for microglial NF-B signaling in mediating tau spreading and toxicity in tauopathy. bulk RNAseq of primary microglia treated with vehicle or tau fibrils; adult microglia isolated from 11-month-old male non-transgenic control mice and PS19 mice; primary microglia with endogenous IKKβ expression or IKKβCA overexpression and primary microglia with wildtype IKKβ expression or deletion of IKKβ; cortical tissues from Ikbkb+/+, Ikbkb-/-, IkbkbWT, IkbkbCA, Ikbkb+/+;P301S+ and Ikbkb-/-;P301S+ male mice