Soluble pathogenic tau transmission to astrocytes drives acute oxidative damage, cellular senescence, and neurovascular uncoupling in a model of Alzheimers tauopathy

We previously found that soluble pathogenic tau aggregates (tau oligomers) enter brain microvascular endothelial cells and induce cellular senescence and microvascular dysfunction in a tauopathy mouse model. This study shows that soluble pathogenic tau is also transmitted to astrocytes, where it induces mitochondrial dysfunction, mediates senescence, and impairs neurovascular coupling responses. Single-cell RNA sequencing of hTau mouse cortex revealed astrocytes as one of the most transcriptionally altered cell type, showing coordinated downregulation of electron transport chain genes and upregulation of stress-induced and inflammatory markers, also elevated in hTau mouse brain and astrocyte-enriched fractions. Similar to neuron-to-neuron transmission, soluble tau aggregates entered primary human astrocytes via a heparin-sensitive process, causing microtubule destabilization, ATP depletion, and mitochondrial ROS accumulation before induction of cell-cycle-arrest-associated markers. Mitochondrial ROS scavenging with Mito TEMPO reduced tau-induced SASP cytokine activation in astrocytes in vitro and in vivo. Coculturing neurons with astrocytes undergoing tau induced senescence decreased dendritic spine density, branch level, and dendritic area in a non-cell-autonomous manner. Tau and the SASP-associated cytokines IL-1{beta} and IL-6 contributed to distinct aspects of the neuronal structural phenotype. Astrocyte-targeted SOD2 overexpression attenuated the hTau-related deficit in evoked cerebral blood flow responses; however, this partial improvement in response magnitude and duration did not achieve statistical significance compared to hTau mice expressing GFP. These results identify astrocyte senescence as a potential mechanism connecting astrocyte tau uptake, mitochondrial stress, and neuronal structural impairment. The findings motivate further study of mitochondrial antioxidant defense in tau-associated astrocyte dysfunction.