Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice

Abstract Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, and is released into the extracellular space. Microglia are the first responders to the extracellular tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis and activate innate immune response gene expression by nuclear factor-kappa B (NF-κB). However, longitudinal NF-κB activation in tauopathies and whether pathological tau (pTau) contributes to NF-κB activity is unknown. Here, we tau oligomers from human Alzheimer’s disease brain (AD-TO) activate NF-κB in mouse microglia and macrophages reducing the IκBα via promoting its secretion in the extracellular space. NF-κB activity peaks at 9- and 11-months age in PS19Luc + and hTauLuc + mice, respectively. Reducing pTau via pharmacological (DOX), genetic ( Mapt -/- ) or antibody-mediated neutralization (immunization with pT181-Qβ vaccine) reduces NF-κB activity, and together suggest pTau is a driver of NF-κB and chronic neuroinflammation tauopathies. Summary Neuronal tau activates microglial NF-κB constitutively by secreting its inhibitor IκBα. NF-κB activation in PS19Luc + and hTauLuc + mice peaks at 9- and 11-months of age, respectively. Neutralizing pTau with pT181-Qβ vaccine (targeting phosphorylated threonine 181 tau) alleviates NF-κB activity in tauopathy mice.