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Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer’s Disease Models
Ruiz-Uribe NE, Alfadhel M, Wolf N, Murray SE, Gross E, Devine A, Shaby DG, Belali S et al.. bioRxiv, 2026-10-16
Topic: Plasma and spinal-fluid biomarkers
Vascular dysfunction is increasingly recognized as a feature of Alzheimer’s disease (AD), and inadequate oxygen delivery may contribute to neuronal death. However, the relationship between cerebral oxygenation and neuronal pathology remains unclear. Here, we used two-photon phosphorescence lifetime microscopy (2PLM) with Oxyphor2P to measure intravascular and tissue partial pressure of oxygen (pO2) at three cortical depths (0, 100 and 200 µm) in awake rTg4510 and THY-Tau22 mice. In 9-month-old rTg4510 mice, capillary and venular pO2 were lower than in WT, mainly in deeper layers, and oxygen extraction fraction was increased, whereas 6-month-old mice showed increases in capillary and venular pO2. Suppressing the tau transgene with doxycycline for three months did not restore vascular pO2. THY-Tau22 mice, despite limited tangle pathology, showed even greater reductions in capillary pO2 at every depth. In 6-month-old rTg4510 mice, tissue pO2 trended lower than in WT mice, and the fraction of low pO2 values (< 18 mmHg) increased with depth, reaching 33% at 200 µm versus 4% in WT. By labeling neurofibrillary tangles (NFTs) with the tau-binding dye HS84, we found that tissue pO2 was significantly lower in tangle-positive areas at 100 and 200 µm. Longitudinal imaging of 2,282 neurons showed that disappearing neurons were not located in relatively hypoxic tissue within an animal. Finally, ex vivo immunostaining revealed neuronal loss and increased astrogliosis in rTg4510 mice, while vascular architecture was unchanged. Altogether, our results indicate that tau disrupts cerebrovascular and tissue oxygenation in a depth- and age-dependent manner, and that neuronal loss is not explained by the oxygen levels of a neuron’s immediate microenvironment but may instead reflect a global reduction in cortical oxygenation.
Key findings
- In 6-month-old rTg4510 mice, tissue pO2 trended lower than in WT mice, and the fraction of low pO2 values (< 18 mmHg) increased with depth, reaching 33% at 200 µm versus 4% in WT.
- By labeling neurofibrillary tangles (NFTs) with the tau-binding dye HS84, we found that tissue pO2 was significantly lower in tangle-positive areas at 100 and 200 µm.
- Longitudinal imaging of 2,282 neurons showed that disappearing neurons were not located in relatively hypoxic tissue within an animal.
- Finally, ex vivo immunostaining revealed neuronal loss and increased astrogliosis in rTg4510 mice, while vascular architecture was unchanged.
- Altogether, our results indicate that tau disrupts cerebrovascular and tissue oxygenation in a depth- and age-dependent manner, and that neuronal loss is not explained by the oxygen levels of a neuron’s immediate microenvironment but may instead reflect a global reduction in cortical oxygenation.
Study details
- Study designlongitudinal study
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 35 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for 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 22 of the 62 points we could judge it on, which is 35 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 | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” 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 | 22 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 22 of the 62 points we could judge it on is 35 out of 100. |
| Total | 35 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Ruiz-Uribe, N. E., Alfadhel, M., Wolf, N., Murray, S. E., Gross, E., Devine, A., et al. (2026). Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer’s Disease Models. bioRxiv. https://doi.org/10.64898/2026.10.09.757981
Vancouver
Ruiz-Uribe NE, Alfadhel M, Wolf N, Murray SE, Gross E, Devine A, et al. Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer’s Disease Models. bioRxiv. 2026. doi:10.64898/2026.10.09.757981.
BibTeX
@article{ruizuribe2026-e2da99b8,
author = {Ruiz-Uribe, N. E. and Alfadhel, M. and Wolf, N. and Murray, S. E. and Gross, E. and Devine, A. and Shaby, D. G. and Belali, S. and others},
title = {{Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer’s Disease Models}},
journal = {bioRxiv},
year = {2026},
doi = {10.64898/2026.10.09.757981},
url = {https://doi.org/10.64898/2026.10.09.757981}
}