NF-κB signaling drives microglial-mediated tau spreading and toxicity in a mouse model of tauopathy Chao Wang1, Yaqiao Li1, David Le1, Yungui Zhou1, Lihong Zhan1, Lay Kodama1, Marcus Chin1, Sue-Ann Mok2, Jason Gestwicki2, Li Gan1, * 1Gladstone Institutes of Neurological Disease, Department of Neurology; 2Institute for Neurodegenerative Disease, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California *Corresponding Author
Tauopathies are a class of neurodegenerative diseases characterized by intracellular accumulation of pathological tau inclusions. With disease progression, pathological tau can also spread across different brain regions. Remarkable neuroinflammation is linked with tauopathy even in early disease stage. Although accumulated evidence suggests that activated microglia, major cellular components of CNS inflammation, are associated with tauopathy, whether activated microglia can cause neuronal toxicity and drive tau spreading remains unknown. NF-κB is a central regulator of microglia activation and its activity is regulated by ikkβ. We found that tau activated NF-κB signaling in microglia. Inactivation of NF-κB signaling by genetic deletion of ikkβ in microglia rescued spatial learning and memory deficits in PS19 mouse model of tauopathy, while chronic activation of NF-κB in microglia by overexpressing constitutively active form of ikkβ is sufficient to cause functional deficits. Surprisingly, pathological tau levels were not correlated with functional deficits, indicating the presence of tau independent neurotoxicity. Tau spreading, induced by inoculation of synthetic tau fibrils into PS19 mice, was dramatically halted by inactivation of microglial NF-κB signaling or depletion of microglia. Moreover, activation of NF-κB signaling in microglia promoted tau spreading. To elucidate underlying mechanism, we established a high-content analysis platform using primary microglia and neurons. We found that microglia processed tau fibrils and secreted acetylated tau fragments, which was accelerated by activation of NF-κB signaling. Co-culturing microglia with neurons significantly increased tau spreading in neurons. Our data suggest that activated microglia directly cause neurotoxicity and mediate tau spreading by processing and releasing tau fragments, which is regulated by NF-κB signaling pathway. Targeting NF-κB signaling pathway in microglia may lead to novel therapeutic approach for tauopathies.
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