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Updated: Sep 27, 2025
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Chao Wang1, Li Fan2, Rabia R Khawaja3
1Gladstone Institutes, University of California, San Francisco, San Francisco, CA, USA.
Abstract:
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.
Insights
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity in tauopathies. Inhibiting microglial NF-κB in mice improved memory and reduced tau spread.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia activation is a key feature of tauopathies like Alzheimer's disease.
- The precise role of microglia activation in tau toxicity is not fully understood.
Purpose of the Study:
- To investigate the role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling in microglia-mediated tau propagation and toxicity.
- To determine the therapeutic potential of targeting microglial NF-κB signaling in tauopathy.
Main Methods:
- Utilized PS19 mouse models of tauopathy with varying NF-κB activation states.
- Employed primary microglia cultures to study tau fibril uptake and release.
- Conducted behavioral tests, transcriptomic analysis, and single-cell RNA sequencing.
Main Results:
- Activated NF-κB signaling in microglia exacerbates tau seeding and spreading.
- Inhibition of NF-κB reduces tau fibril release from microglia and rescues autophagy deficits.
- Inactivating microglial NF-κB in aged mice improves cognitive function and alters transcriptomic profiles.
Conclusions:
- Microglial NF-κB signaling is a critical mediator of tau propagation and toxicity in tauopathies.
- Targeting microglial NF-κB represents a potential therapeutic strategy for Alzheimer's disease and related tauopathies.
