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Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau
Abhirami Kannan Iyer, Lisa Vermunt, Farzaneh Sadat Mirfakhar, Miguel Minaya, Mariana Acquarone, Rama K. Koppisetti, Arun Renganathan, Shih‐Feng You et al.. Molecular Psychiatry, 2025-06-17
Topic: Brain proteins, microglia and lab models
Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that MAPT mRNA and tau protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the MAPT IVS10 + 16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that MAPT IVS10 + 16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from MAPT IVS10 + 16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed in vitro were recapitulated in human brain tissue and cerebrospinal fluid from MAPT mutations carriers. Together, our findings that MAPT IVS10 + 16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutics for tauopathies.
Key findings
- Additionally, we found that secretory factors from MAPT IVS10 + 16 iMGLs impact neuronal health, reducing synaptic density in neurons.
- Together, our findings that MAPT IVS10 + 16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutics for tauopathies.
Why it matters
In a stem cell model, microglia carrying a MAPT mutation showed abnormalities including stalled phagocytosis and disrupted TREM2/TYROBP networks, and factors they released reduced synaptic density in neurons. The authors say this has implications for developing therapeutics for tauopathies, but this is laboratory work, not a treatment.
Study details
- Evidence strengthLow
How this study scored 45/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular Psychiatry) |
| Journal's citation record | 3 / 4 | Molecular Psychiatry: journal h-index 318 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 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 | 2 / 7 | Cited 9 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 3.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Celeste M M. Karch: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40527900) |
| Free to read | 2 / 2 | Free to read |
| Total | 45 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41380-025-03073-2
- PubMed: 40527900
- Original source →
- Free full text: Molecular Psychiatry →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Iyer, A. K., Vermunt, L., Mirfakhar, F. S., Minaya, M., Acquarone, M., Koppisetti, R. K., et al. (2025). Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau. Molecular Psychiatry. https://doi.org/10.1038/s41380-025-03073-2
Vancouver
Iyer AK, Vermunt L, Mirfakhar FS, Minaya M, Acquarone M, Koppisetti RK, et al. Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau. Molecular Psychiatry. 2025. doi:10.1038/s41380-025-03073-2. PMID: 40527900.
BibTeX
@article{iyer2025-40527900,
author = {Iyer, Abhirami Kannan and Vermunt, Lisa and Mirfakhar, Farzaneh Sadat and Minaya, Miguel and Acquarone, Mariana and Koppisetti, Rama K. and Renganathan, Arun and You, Shih‐Feng and others},
title = {{Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau}},
journal = {Molecular Psychiatry},
year = {2025},
doi = {10.1038/s41380-025-03073-2},
pmid = {40527900},
url = {https://doi.org/10.1038/s41380-025-03073-2}
}
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