|Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.
|Year of Publication
|Wang C, Fan L, Khawaja RR, Liu B, Zhan L, Kodama L, Chin M, Li Y, Le D, Zhou Y, Condello C, Grinberg LT, Seeley WW, Miller BL, Mok S-A, Gestwicki JE, Cuervo AMaria, Luo W, Gan L
|2022 04 12
|Animals, Mice, Microglia, NF-kappa B, tau Proteins, Tauopathies
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.
|PubMed Central ID
|U54 NS100717 / NS / NINDS NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
R01 NS059690 / NS / NINDS NIH HHS / United States
K12 GM102779 / GM / NIGMS NIH HHS / United States
R01 AG072758 / AG / NIA NIH HHS / United States
R01 AG051390 / AG / NIA NIH HHS / United States
R01 AG054214 / AG / NIA NIH HHS / United States
R01 AG064239 / AG / NIA NIH HHS / United States
F30 AG062043 / AG / NIA NIH HHS / United States