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A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females
Chen X, Munoz-Mayorga D, Lyu X, Jati S, Zhang J, Rossitto L, Tao Y, Zhao S et al.. Research Square, 2026-07-16
Topic: Inflammation, microglia and astrocytes
Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT–TR4– Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.
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APA 7th
Chen, X., Munoz-Mayorga, D., Lyu, X., Jati, S., Zhang, J., Rossitto, L., et al. (2026). A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females. Research Square. https://doi.org/10.21203/rs.3.rs-10286730/v1
Vancouver
Chen X, Munoz-Mayorga D, Lyu X, Jati S, Zhang J, Rossitto L, et al. A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females. Research Square. 2026. doi:10.21203/rs.3.rs-10286730/v1.
BibTeX
@article{chen2026-b03c3c29,
author = {Chen, X. and Munoz-Mayorga, D. and Lyu, X. and Jati, S. and Zhang, J. and Rossitto, L. and Tao, Y. and Zhao, S. and others},
title = {{A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10286730/v1},
url = {https://doi.org/10.21203/rs.3.rs-10286730/v1}
}
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Key findings
- Together, our findings uncover a non-canonical DHT–TR4– Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.
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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, 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 (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 | 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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