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Soluble pathogenic tau transmission to astrocytes drives cellular senescence and neurovascular uncoupling in a model of Alzheimer’s tauopathy
Makhlouf H, Dorigatti AO, Hernandez S, de Rosa N, Miller L, Hussong S, Holstein D, Lechleiter J et al.. bioRxiv, 2026-09-12
Topic: Disease mechanisms in lab and animal studies
Pathogenic tau oligomers are transmitted between neurons and non-neuronal cells and may contribute to cellular dysfunction in Alzheimer’s 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.
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APA 7th
Makhlouf, H., Dorigatti, A. O., Hernandez, S., de Rosa, N., Miller, L., Hussong, S., et al. (2026). Soluble pathogenic tau transmission to astrocytes drives cellular senescence and neurovascular uncoupling in a model of Alzheimer’s tauopathy. bioRxiv. https://doi.org/10.64898/2026.09.08.750215
Vancouver
Makhlouf H, Dorigatti AO, Hernandez S, de Rosa N, Miller L, Hussong S, et al. Soluble pathogenic tau transmission to astrocytes drives cellular senescence and neurovascular uncoupling in a model of Alzheimer’s tauopathy. bioRxiv. 2026. doi:10.64898/2026.09.08.750215.
BibTeX
@article{makhlouf2026-4949dd36,
author = {Makhlouf, H. and Dorigatti, A. O. and Hernandez, S. and de Rosa, N. and Miller, L. and Hussong, S. and Holstein, D. and Lechleiter, J. and others},
title = {{Soluble pathogenic tau transmission to astrocytes drives cellular senescence and neurovascular uncoupling in a model of Alzheimer’s tauopathy}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.09.08.750215},
url = {https://doi.org/10.64898/2026.09.08.750215}
}
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Key findings
- 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.
- 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.
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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