Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice
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Updated: May 17, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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.
Insights
Pathological tau (pTau) drives chronic neuroinflammation in tauopathies by activating microglial nuclear factor-kappa B (NF-κB). Reducing pTau levels alleviates NF-κB activity, suggesting pTau as a key therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Tau pathology is central to tauopathies, with hyperphosphorylated tau (pTau) detaching from microtubules and aggregating.
- Extracellular pTau acts as a damage-associated molecular pattern (DAMP), activating microglia and the innate immune response via nuclear factor-kappa B (NF-κB).
- The longitudinal dynamics of NF-κB activation and the specific role of pTau in this process within tauopathies remain unclear.
Purpose of the Study:
- To investigate the longitudinal activation of NF-κB in mouse models of tauopathy.
- To determine if pathological tau (pTau) directly contributes to NF-κB activation.
- To explore therapeutic strategies targeting pTau to modulate NF-κB activity and neuroinflammation.
Main Methods:
- Utilized PS19Luc+ and hTauLuc+ mouse models of tauopathy.
- Administered human Alzheimer's disease brain-derived tau oligomers (AD-TO) to mouse microglia and macrophages.
- Assessed NF-κB activity by measuring IκBα levels and secretion.
- Employed pharmacological (DOX), genetic ( Mapt knockout), and antibody-mediated (pT181-Qβ vaccine) interventions to reduce pTau.
Main Results:
- Extracellular tau oligomers activate NF-κB in microglia and macrophages by promoting IκBα secretion.
- NF-κB activation exhibited peak activity at 9 months in PS19Luc+ mice and 11 months in hTauLuc+ mice.
- Pharmacological, genetic, and antibody-mediated reduction of pTau significantly decreased NF-κB activity.
Conclusions:
- Pathological tau (pTau) is a key driver of NF-κB activation and chronic neuroinflammation in tauopathies.
- pTau directly activates microglial NF-κB signaling, contributing to the disease pathology.
- Targeting pTau represents a promising therapeutic strategy for mitigating neuroinflammation in tauopathies.
