Tangavelou Karthikeyan, Jiang Shanya, Dadras Somayeh, Hulse Jonathan P, Sanchez Kathryn, Bondu Virginie, Villaseñor Zachary, Mandell Michael, Peabody Julianne, Chackerian Bryce, Bhaskar Kiran
bioRxiv. 2025 Mar 13:2025.03.10.642500. doi: 10.1101/2025.03.10.642500.
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 ( ) 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.
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.
tau蛋白调节神经元完整性。在tau蛋白病中，磷酸化的tau蛋白从微管上脱离并聚集，然后释放到细胞外空间。小胶质细胞是细胞外tau蛋白的第一反应者，tau蛋白是一种与危险/损伤相关的分子模式（DAMP），可通过蛋白质稳态清除，并通过核因子κB（NF-κB）激活先天免疫反应基因表达。然而，tau蛋白病中NF-κB的纵向激活以及病理性tau蛋白（pTau）是否有助于NF-κB活性尚不清楚。在这里，我们发现来自人类阿尔茨海默病大脑的tau寡聚体（AD-TO）在小鼠小胶质细胞和巨噬细胞中激活NF-κB，通过促进其在细胞外空间的分泌来降低IκBα。在PS19Luc和hTauLuc小鼠中，NF-κB活性分别在9个月和11个月大时达到峰值。通过药理学（多西环素）、遗传学（ ）或抗体介导的中和作用（用pT181-Qβ疫苗免疫）降低pTau可降低NF-κB活性，这共同表明pTau是NF-κB和慢性神经炎症性tau蛋白病的驱动因素。
神经元tau蛋白通过分泌其抑制剂IκBα持续激活小胶质细胞NF-κB。PS19Luc和hTauLuc小鼠中的NF-κB激活分别在9个月和11个月大时达到峰值。用pT181-Qβ疫苗（靶向磷酸化苏氨酸181 tau）中和pTau可减轻tau蛋白病小鼠的NF-κB活性。
