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Updated: Jun 9, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer's
Alberto Ardura-Fabregat1,2, Lance Fredrick Pahutan Bosch1,2, Emile Wogram1
1Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Abstract:
Microglial spatial heterogeneity remains a crucial yet not fully answered question in the context of potential cell-directed therapies for Alzheimer's disease (AD). There is an unclear understanding of the dynamics of distinct microglia states adjacent to or far from amyloid-beta (Aβ) plaques and their contributions to neurodegenerative diseases. Here we combine multicolor fluorescence cell fate mapping, single-cell transcriptional analysis, epigenetic profiling, immunohistochemistry and computational modeling to comprehensively characterize the relation of plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in a mouse model of AD. We show that non-PAM are a distinct and highly dynamic microglial state, transitioning to PAM after Aβ plaque deposition in female mice. Non-PAM modulate the cell population expansion in response to amyloid deposition and rapidly respond to environmental cues. Indeed, Csf1 signaling modulates non-PAM-to-PAM transition during disease progression. Our data suggest that microglia states and their dynamics between each other can have distinct contributions to disease, and they may be targeted for the treatment of AD.
Insights
Non-plaque-associated microglia (non-PAM) in Alzheimer's disease (AD) are a dynamic state that transition to plaque-associated microglia (PAM). This transition, influenced by Csf1 signaling, offers potential therapeutic targets for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglial spatial heterogeneity is critical for Alzheimer's disease (AD) pathogenesis.
- Distinct microglia states near and far from amyloid-beta (Aβ) plaques and their roles in neurodegeneration are poorly understood.
Purpose of the Study:
- To comprehensively characterize the relationship and dynamics between plaque-associated microglia (PAM) and non-plaque-associated microglia (non-PAM) in an AD mouse model.
- To elucidate the contribution of distinct microglial states to AD progression.
Main Methods:
- Multicolor fluorescence cell fate mapping
- Single-cell transcriptional and epigenetic profiling
- Immunohistochemistry and computational modeling
Main Results:
- Non-PAM represent a distinct, dynamic microglial state that transitions to PAM following Aβ plaque deposition in female mice.
- Non-PAM regulate cell population expansion in response to amyloid deposition and environmental cues.
- Cerebrospinal fluid 1 (Csf1) signaling modulates the non-PAM to PAM transition during disease progression.
Conclusions:
- Microglial states and their dynamic transitions play distinct roles in AD.
- Targeting specific microglial states and their dynamics may offer novel therapeutic strategies for Alzheimer's disease.
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