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Updated: Sep 19, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Cell autonomous microglia defects in a stem cell model of frontotemporal dementia tau
Abhirami K Iyer1, Lisa Vermunt2, Farzaneh S Mirfakhar1
1Department of Psychiatry, Washington University in St Louis, St Louis, MO, USA.
Abstract:
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.
Insights
Tau mutations directly impair microglia function, affecting neuronal health in tauopathies. This study reveals cell-intrinsic microglial defects and their impact on neurons, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Neuronal dysfunction is a hallmark of neurodegenerative tauopathies.
- Immune cells, particularly microglia, are increasingly recognized for their active role in disease progression across neurodegenerative conditions.
Purpose of the Study:
- To investigate the expression and functional impact of tau in microglia.
- To determine if tau mutations cause cell-intrinsic microglial dysfunction and affect neuronal health.
Main Methods:
- Analysis of MAPT mRNA and tau protein expression in human brain microglia and induced pluripotent stem cell-derived microglia-like cells (iMGLs).
- Utilizing iMGLs with a specific MAPT mutation (IVS10+16) and isogenic controls to assess microglial transcriptional states and function.
- Assessing cytoskeletal integrity, phagocytosis, TREM2/TYROBP network activity, and metabolism in mutant microglia.
- Evaluating the impact of iMGL secretory factors on neuronal health and synaptic density.
- Correlating in vitro findings with human brain tissue and cerebrospinal fluid from MAPT mutation carriers.
Main Results:
- MAPT mRNA and tau protein are expressed in human microglia and iMGLs.
- The MAPT IVS10+16 mutation induces distinct transcriptional states and cell-intrinsic dysfunction in microglia, including cytoskeletal abnormalities, impaired phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism.
- Secretory factors from mutant microglia negatively impact neuronal health, reducing synaptic density.
- In vitro findings were mirrored in human samples from MAPT mutation carriers.
Conclusions:
- Tau mutations directly drive cell-intrinsic dysfunction in microglia.
- Microglial dysfunction originating from tau mutations contributes to neuronal pathology in tauopathies.
- These findings highlight microglia as a critical cellular target for developing novel tauopathy therapeutics.
