Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.
Chao WangLi FanRabia R KhawajaBangyan LiuLihong ZhanLay KodamaMarcus Y ChinYaqiao LiDavid LeYungui ZhouCarlo CondelloLea Tenenholz GrinbergWilliam W SeeleyBruce L MillerSue-Ann MokJason E GestwickiAna Maria CuervoWenjie LuoLi GanPublished in: Nature communications (2022)
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.
Keyphrases
- lps induced
- nuclear factor
- inflammatory response
- cerebrospinal fluid
- signaling pathway
- toll like receptor
- single cell
- oxidative stress
- rna seq
- neuropathic pain
- lipopolysaccharide induced
- pi k akt
- mouse model
- transcription factor
- type diabetes
- high throughput
- cognitive decline
- metabolic syndrome
- deep learning
- skeletal muscle
- middle aged