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.