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NADPH attenuates tau pathology and disease-associated microglial phenotype in a truncated tau- induced mouse model
Da J, Zhang R, Xu L, Wu R, Zhang S, Wang H, Baazaoui N, Shi J et al.. Research Square, 2026-10-19
Topic: Inflammation, microglia and astrocytes
Truncated tau is increasingly recognized as a pivotal pathogenic event in Alzheimer’s disease (AD). Although the 151–391 fragment (tau Tr ) exhibits strong pathological capacity, whether tau Tr is sufficient to induce a redox-inflammatory brain response in vivo and whether this response is therapeutically modifiable remain unclear. Here, we show that tau Tr drives robust aggregation and hyperphosphorylation in vitro , and induces pronounced tau pathology accompanied by microglial activation in vivo . Transcriptomic profiling further revealed that tau Tr elicits a ROS-associated and pro-inflammatory program, characterized by activation of NF-κB signaling and closely resembling transcriptional signatures observed in tau transgenic models. Notably, NADPH treatment markedly attenuated tau Tr aggregation and hyperphosphorylation in vitro , and significantly reduced tau pathology and microglial activation in vivo . At the molecular level, NADPH treatment was associated with reduced expression of genes involved in ROS production, neuroinflammation, and microglial activation, including markers related to disease-associated microglia and led to the normalization of microglial morphology and the decreased proportion of Dectin-1 and TREM2-positive microglia. Together, these findings demonstrate that truncated tau is sufficient to drive a ROS-NF-κB-dependent neuroinflammatory microglial program in vivo , and that NADPH can partially reverse this pathogenic cascade, highlighting redox modulation as a potential therapeutic strategy in tau-related neuroinflammation.
Key findings
- Transcriptomic profiling further revealed that tau Tr elicits a ROS-associated and pro-inflammatory program, characterized by activation of NF-κB signaling and closely resembling transcriptional signatures observed in tau transgenic models.
- Notably, NADPH treatment markedly attenuated tau Tr aggregation and hyperphosphorylation in vitro , and significantly reduced tau pathology and microglial activation in vivo .
- At the molecular level, NADPH treatment was associated with reduced expression of genes involved in ROS production, neuroinflammation, and microglial activation, including markers related to disease-associated microglia and led to the normalization of microglial morphology and the decreased proportion of Dectin-1 and TREM2-positive microglia.
- Together, these findings demonstrate that truncated tau is sufficient to drive a ROS-NF-κB-dependent neuroinflammatory microglial program in vivo , and that NADPH can partially reverse this pathogenic cascade, highlighting redox modulation as a potential therapeutic strategy in tau-related neuroinflammation.
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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 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 (Research Square) |
| 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 | Laboratory or animal study (title names “mouse”) — scores zero |
| 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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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Da, J., Zhang, R., Xu, L., Wu, R., Zhang, S., Wang, H., et al. (2026). NADPH attenuates tau pathology and disease-associated microglial phenotype in a truncated tau- induced mouse model. Research Square. https://doi.org/10.21203/rs.3.rs-11151367/v1
Vancouver
Da J, Zhang R, Xu L, Wu R, Zhang S, Wang H, et al. NADPH attenuates tau pathology and disease-associated microglial phenotype in a truncated tau- induced mouse model. Research Square. 2026. doi:10.21203/rs.3.rs-11151367/v1.
BibTeX
@article{da2026-559eb37f,
author = {Da, J. and Zhang, R. and Xu, L. and Wu, R. and Zhang, S. and Wang, H. and Baazaoui, N. and Shi, J. and others},
title = {{NADPH attenuates tau pathology and disease-associated microglial phenotype in a truncated tau- induced mouse model}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11151367/v1},
url = {https://doi.org/10.21203/rs.3.rs-11151367/v1}
}
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