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

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

Nature communications (2022-04-14)
Chao Wang, Li Fan, Rabia R Khawaja, Bangyan Liu, Lihong Zhan, Lay Kodama, Marcus 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 Maria Cuervo, Wenjie Luo, Li Gan
摘要

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.

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泰莫西芬, ≥99%
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4-Hydroxytamoxifen Ready Made Solution, 5 mg/mL in ethanol: isopropanol (95:5)