Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau
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.
Authors
- Shih‐Feng You (ORCID: https://orcid.org/0000-0001-8713-3815)
- Lea T. Grinberg (ORCID: https://orcid.org/0000-0002-6809-0618)
- Lisa Vermunt (ORCID: https://orcid.org/0000-0001-7420-6384)
- Celeste M M. Karch (ORCID: https://orcid.org/0000-0002-6854-5547)
- Arun Renganathan (ORCID: https://orcid.org/0000-0002-6722-8136)
- Alissa L. Nana (ORCID: https://orcid.org/0000-0003-3474-8044)
- Chihiro Sato (ORCID: https://orcid.org/0000-0002-7639-8727)
- Miguel Minaya (ORCID: https://orcid.org/0000-0002-2573-6087)
- Grant Galasso
- Salvatore Spina (ORCID: https://orcid.org/0000-0003-3570-9143)
- Scott M. Lee (ORCID: https://orcid.org/0000-0002-6607-0541)
- Jacob Marsh (ORCID: https://orcid.org/0000-0003-3576-6949)
- Farzaneh S. Mirfakhar (ORCID: https://orcid.org/0000-0002-8392-7244)
- Kylie J. Schache (ORCID: https://orcid.org/0000-0002-9984-0717)
- Abhirami K. Iyer (ORCID: https://orcid.org/0000-0003-1914-6045)
- Guangming Huang (ORCID: https://orcid.org/0000-0002-8391-4013)
- Emma Danhash
- Mariana Acquarone
- William W. Seeley (ORCID: https://orcid.org/0000-0003-1410-2027)
- Charlotte Elisabeth Teunissen (ORCID: https://orcid.org/0000-0002-4061-0837)
- Rama K. Koppisetti (ORCID: https://orcid.org/0000-0002-7539-4572)
- Sally Temple (ORCID: https://orcid.org/0000-0001-7301-783X)
- Anthony Verbeck
- Katherine Miller (ORCID: https://orcid.org/0000-0003-1438-5717)
Institutions
- Universidade de São Paulo (BR)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Neural Stem Cell Institute (US)
- Amsterdam Neuroscience (NL)
- Hope Center for Neurological Disorders (US)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-06-17
- DOI
- https://doi.org/10.1038/s41380-025-03073-2
- Citations
- 2
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- Eli Lilly and Company
- BrightFocus Foundation
- Rensselaer Polytechnic Institute
- Washington University in St. Louis
- Foundation for Barnes-Jewish Hospital
- Children's Discovery Institute
- Hope Center for Neurological Disorders
- GHR Foundation
- Rainwater Charitable Foundation
- Amsterdam University Medical Centers
- ZonMw
- Stichting Dioraphte
- National Institutes of Health
- University of California, San Francisco
- Center for Cellular Imaging, Washington University
- National Institute on Aging
- National Institute of Mental Health
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke