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

Authors

Galvan, V., makhlouf, H., Miller, l., logan, s., Dorigatti, A., Hernandez, S., de Rosa, N., Hussong, S., Kayed, R., Holstein, D., Lechleiter, J.

Abstract

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.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 13 Sep 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.