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Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
- Publication Year :
- 2021
- Publisher :
- Cold Spring Harbor Laboratory, 2021.
-
Abstract
- Activation of microglia, the brain’s innate immune cells, 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 PS19 mice, consistent with the observation that NF-κB activation accelerates processing of internalized tau fibrils in primary microglia. Remarkably, inhibition of microglial NF-κB specifically also rescued tau-mediated learning and memory deficits, and restored overall transcriptomic changes while increasing tau inclusions. On a single cell level, we discovered 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 central role for microglial NF-κB signaling in mediating tau toxicity in tauopathy.
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........29d36224b5351f3eaf619107ba55d7bb