Response of spatially defined microglia states with distinct chromatin accessibility in a mouse model of Alzheimer’s disease
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.
Authors
- Omar Mossad (ORCID: https://orcid.org/0000-0003-4329-7804)
- Daniel Schnepf (ORCID: https://orcid.org/0000-0002-7528-981X)
- Roman Sankowski (ORCID: https://orcid.org/0000-0001-9215-8021)
- Sebastian Preißl (ORCID: https://orcid.org/0000-0001-8971-5616)
- Andrew J. Macpherson (ORCID: https://orcid.org/0000-0002-7192-0184)
- Marco Prinz (ORCID: https://orcid.org/0000-0002-0349-1955)
- Dilara Hasavci
- Nicola Iovino (ORCID: https://orcid.org/0000-0002-3335-7618)
- Philipp Aktories (ORCID: https://orcid.org/0000-0001-7379-791X)
- Hatice Ulupinar
- Daniel C. Brock (ORCID: https://orcid.org/0000-0002-9218-8594)
- Katrin Kierdorf (ORCID: https://orcid.org/0000-0002-9272-4780)
- James Cook (ORCID: https://orcid.org/0000-0002-1905-4928)
- Lance Fredrick Pahutan Bosch (ORCID: https://orcid.org/0000-0002-2741-3855)
- Thomas Blank (ORCID: https://orcid.org/0000-0002-3969-405X)
- Sharon Wald
- Alberto Ardura-Fabregat (ORCID: https://orcid.org/0000-0003-1134-4047)
- Emile Wogram
- Bahtiyar Yılmaz (ORCID: https://orcid.org/0000-0003-1888-9226)
- Lina Kieger
Institutions
- University of Bern (CH)
- University of Graz (AT)
- University of Freiburg (DE)
- University Hospital of Bern (CH)
- University Medical Center Freiburg (DE)
- Max Planck Institute of Immunobiology and Epigenetics (DE)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1038/s41593-025-02006-0
- Citations
- 13
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 10.95