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Updated: Jun 10, 2025
Author Spotlight: Induced Microglia-Like Cell Technology to Shed Light on the Role of Microglial Dysfunction in Neuropsychiatric Disorders
Published on: September 6, 2024
HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures in vitro
Verena Haage1, John F Tuddenham1,2, Alex Bautista1
1Center for Translational & Computational Neuroimmunology, Department of Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center.
Abstract:
Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes1. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans2-6; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate7,8. Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1, LIPA and SCIN as DAM-marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.
Insights
Researchers developed a new method to mimic human disease-associated microglia (DAM) using histone deacetylase (HDAC) inhibitors. This approach helps study DAM roles in neurodegenerative diseases and identify key marker genes.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Disease-associated microglia (DAM) are implicated in neurodegenerative diseases, with distinct subtypes (DAM1, DAM2) identified in mice.
- The role of human DAM in neurodegeneration remains unclear, necessitating better in vitro models.
- Single-cell RNA sequencing has confirmed DAM presence in humans, but their functional significance is debated.
Purpose of the Study:
- To develop a pharmacological method for mimicking human disease-associated microglia (DAM) in vitro.
- To functionally characterize the developed human DAM model.
- To identify shared DAM marker genes across different studies and model systems.
Main Methods:
- Utilized human microglia models exposed to specific histone deacetylase (HDAC) inhibitors.
- Employed a pharmacological approach to induce a DAM phenotype in vitro.
- Analyzed changes in gene expression, amyloid beta phagocytosis, and MCP-1 secretion.
Main Results:
- Successfully mimicked human DAM in vitro using HDAC inhibitors.
- Observed increased amyloid beta phagocytosis and reduced MCP-1 secretion in the model.
- Identified MITF as a key transcription factor driving the DAM phenotype and validated CADM1, LIPA, and SCIN as shared DAM marker genes.
Conclusions:
- The pharmacological strategy effectively models human DAM in vitro.
- This approach facilitates the study of human DAM function and biology in neurodegeneration.
- Identified novel and validated existing DAM marker genes, advancing the understanding of microglial responses.
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