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

• Published in: Nature communications Vol. 13; no. 1; pp. 1969 - 19
• Main Authors: Wang, Chao, Fan, Li, Khawaja, Rabia R., Liu, Bangyan, Zhan, Lihong, Kodama, Lay, Chin, Marcus, Li, Yaqiao, Le, David, Zhou, Yungui, Condello, Carlo, Grinberg, Lea T., Seeley, William W., Miller, Bruce L., Mok, Sue-Ann, Gestwicki, Jason E., Cuervo, Ana Maria, Luo, Wenjie, Gan, Li
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-04-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 38; 38/91; 631/378/2611; 631/378/371; 692/617/375/365/1283; Alzheimer's disease; Animals; Autophagy; Deactivation; Fibrils; Humanities and Social Sciences; Inactivation; Inclusions; Learning; Lymphocytes B; Mice; Microglia; Microglia - metabolism; Microglia - pathology; multidisciplinary; Neurodegenerative diseases; NF-kappa B - metabolism; NF-κB protein; Protein seeding; Science; Science (multidisciplinary); Signaling; Spatial discrimination learning; Spatial memory; Spreading; Tau protein; tau Proteins - metabolism; Tauopathies - metabolism; Tauopathies - pathology; Toxicity; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• 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.
Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.