|Title||Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, Condello C, Grinberg LT, Seeley WW, Miller BL, Mok S-A, Gestwicki JE, Cuervo AMaria, Luo W, Gan L|
|Date Published||2022 Apr 12|
|Keywords||Animals, Mice, Microglia, NF-kappa B, Tauopathies|
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.
|Alternate Journal||Nat Commun|