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

作者：Chao Wang, Li Fan, Rabia R. Khawaja, Bangyan Liu, Lihong Zhan, Lay Kodama, Marcus Y. Chin, Yaqiao Li, David Le, Yungui Zhou, Carlo Condello, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Sue‐Ann Mok, Jason E. Gestwicki, Ana María Cuervo, Wenjie Luo, Li Gan · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-29552-6 · 被引用次数：337 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Alzheimer's disease research and treatments、Neurological Disease Mechanisms and Treatments

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.