{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T22:01:59Z","timestamp":1789768919236,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,12]]},"group-title":"Neuroscience","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Pathogenic tau oligomers are transmitted between neurons and non-neuronal cells and may contribute to cellular dysfunction in Alzheimer\u2019s disease (AD). We previously demonstrated that soluble tau aggregates accumulate in brain microvascular endothelial cells, inducing cellular senescence and microvascular dysfunction in a mouse model of tauopathy. Here, we show that soluble pathogenic tau is also transmitted to astrocytes, where it induces mitochondrial oxidative stress and a senescence-associated phenotype (SASP). Single-cell RNA sequencing of hTau mouse cortex identified astrocytes among the most transcriptionally altered cell types, with reduced expression of electron transport chain genes and increased expression of stress and inflammatory markers. This transcriptional pattern was also observed in hTau brain and astrocyte-enriched fractions. Soluble tau aggregates transmitted to primary human astrocytes through a heparin-sensitive process and rapidly decreased ATP levels and increased mitochondrial ROS. These mitochondrial changes preceded detectable microtubule destabilization and were followed by induction of SASP and cell-cycle-arrest-associated markers. Scavenging mitochondrial ROS with MitoTEMPO reduced tau-induced SASP cytokine and senescence-associated responses in vitro and in vivo, supporting a causal contribution of mitochondrial oxidative stress to senescence induction. Neurons cocultured with astrocytes undergoing tau-induced senescence exhibited reduced dendritic spine density, branching, and dendritic area, demonstrating non-cell-autonomous effects on neuronal structure. Astrocyte-targeted SOD2 overexpression ameliorated deficits in evoked cerebral blood-flow responses in hTau mice. Together, these findings identify mitochondrial oxidative stress as a mechanistic link between pathogenic tau transmission and astrocyte senescence-associated dysfunction and implicate impaired mitochondrial antioxidant defense in neuronal and neurovascular abnormalities associated with tauopathy.<\/jats:p>","DOI":"10.64898\/2026.09.08.750215","type":"posted-content","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T13:50:13Z","timestamp":1789221013000},"source":"Crossref","is-referenced-by-count":0,"title":["Soluble pathogenic tau transmission to astrocytes drives cellular senescence and neurovascular uncoupling in a model of Alzheimer\u2019s tauopathy"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2118-7555","authenticated-orcid":false,"given":"Haneen","family":"Makhlouf","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA."},{"name":"Oklahoma City Veterans 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