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Cited by 15Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

Single-nucleus transcriptomics reveals a distinct microglial state and increased MSR1-mediated phagocytosis as common features across dementia subtypes

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Chia, Sook-Yoong, Li, Mengwei, Li, Zhihong, Tu, Haitao, Lee, Jolene Wei Ling, Qiu, Lifeng, Ling, Jingjing, Reynolds, Richard +5 more·2025·Genome Medicine
DOI 10.1186/s13073-025-01519-4PMC PMC12359983
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Abstract

BACKGROUND: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD) collectively represent the majority of dementia cases worldwide. While these subtypes share clinical, genetic, and pathological features, their transcriptomic similarities and differences remain poorly understood. METHODS: We applied single-nucleus RNA-sequencing (snRNA-seq) to prefrontal cortex samples from individuals with non-cognitive impairment control (NCI), and dementia subtypes (AD, DLB, and PDD) to investigate cell type-specific gene expression patterns and pathways underlying pathological similarities and differences across dementia subtypes. SnRNA-seq findings were validated through RNAscope, immunohistochemistry, and additional biochemical analyses in human tissues and cellular models. RESULTS: SnRNA-seq analysis revealed elevated microglial proportions across all dementia subtypes compared to NCI. Further analysis of cell type-specific transcriptomes identified overlapping differentially expressed genes (DEGs) between microglia and oligodendrocytes across all dementia subtypes. While AD showed molecular similarities to NCI, PDD and DLB were clustered more closely together, sharing a greater number of DEGs and related pathways, predominantly associated with microglia. Investigation of interactions between microglia and oligodendrocytes revealed a distinct microglial state in all dementia subtypes. MSR1, a gene encoding a scavenger receptor, was upregulated in microglia across all dementia subtypes, along with its associated gene HSPA1A in oligodendrocytes. RNAscope supported the potential interaction between microglia and oligodendrocytes, where these cells were in closer proximity to each other in human cortical tissues of PDD compared to NCI. MSR1 expression was significantly increased in cortical primary microglia from PD mice compared with non-transgenic (NTg) mice. Additionally, the expression of myelin-associated genes (MBP, MOBP, and PLP1) was significantly upregulated in PD microglia compared to NTg, supporting the presence of the distinct microglia. Furthermore, MSR1-positive microglia colocalised with MBP in cortical tissue of PDD patients, suggesting a functional role of MSR1 in myelin debris clearance. Overexpression of MSR1 in microglial cells enhanced their phagocytic activity toward myelin, and reciprocally, myelin treatment upregulated MSR1 protein levels, indicating enhanced MSR1-mediated myelin phagocytosis. CONCLUSIONS: Our findings provide novel insights into the cell type-specific role of microglial MSR1 in AD, DLB, and PDD, linking its increased phagocytic capacity to myelin defects as a common feature of neurodegenerative dementias.

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  • Microglia may interact with oligodendrocyte-lineage cells in disease-specific ways, as suggested by newer single-nucleus studies across dementia subtypes.

    “newer single-nucleus studies across dementia subtypes suggest that microglia may also interact with oligodendrocyte-lineage cells in disease-specific ways [58,61]”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [61]

  • Spatial transcriptomic studies of plaque niches have highlighted microglia-astrocyte crosstalk around amyloid deposits.

    “Spatial transcriptomic studies of plaque niches have highlighted microglia–astrocyte crosstalk around amyloid deposits”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [61]

    The Results section, “Identification of a distinct state of microglia across dementia subtypes” (page unavailable), describes potential microglia–oligodendrocyte interactions assessed with RNAscope. Searches for spatial transcriptomics, astrocytes, and amyloid plaque niches found no passage in our copy reporting microglia–astrocyte crosstalk around deposits. (LLM, conf=0.77)

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Cited by

Sorted by citations

Authors
Chia, S.-Y., Li, M., Li, Z., Tu, H., Lee, J. W. L., Qiu, L., Ling, J., Reynolds, R., Albani, S., Tan, E.-K., Ng, A. S. L., Chen, J., & Zeng, L.
Affiliations
  • National Neuroscience Institute (SG)
  • Agency for Science, Technology and Research (SG)
  • Duke-NUS Medical School (SG)
  • Nanyang Technological University (SG)
  • National University of Singapore (SG)
  • Singapore General Hospital (SG)
Corresponding author
  • Chen, Jinmiao
  • Zeng, Li
ORCID
Venue
Genome Medicine
Publisher
Springer Science and Business Media LLC
Published
2025-08-18
Volume
17
Issue
1
Pages
92-92
ISSN
1756-994X (ISSN-L)
DOI
10.1186/s13073-025-01519-4
PMC
PMC12359983
OpenAlex
W4413274991
Cited by
15
References
12
Citations by year
2026: 13 · 2025: 2
FWCI
5.41
Type
journal article
Language
en
Update notices
correction (2025-08-27)
Open access
Licence
Locations
  • Genome Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DR-NTU (Nanyang Technological University) (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Medical Research Council Open Fund-Large Collaborative Grant (LCG002–SPARK II, NMRC/OFLCG/002/2018)
  • Clinician Scientist Individual Research Grant (MOH-CIRG21nov-0001, CIRG19may0052)
  • Open Fund-Individual Research Grant (OFIRG23jul-0075)
  • NMRC Awarded Projects Talent Development (MOH-STaR19nov-0002)
  • Duke-NUS and SingHealth AMC core funding as well as Singapore Ministry of Health’s NMRC under its Centre Grant Program (MOH-000988)
  • A*STAR (A*STAR PEC21-H22P0M0003)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease dementia, microglia, microglial states, MSR1, myelin phagocytosis, myelin debris clearance, prefrontal cortex, single-nucleus transcriptomics, cell type-specific gene expression, HSPA1A
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Dementia, Female, Humans, Male, Phagocytosis, Microglia, Gene Expression Profiling, Scavenger Receptors, Class A, Mice, Single-Cell Analysis, Transcriptome

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