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Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease
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Background: Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer’s disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. Methods: To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Results: Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Conclusions: Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.
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![Fig. 1 Disease associated microglia resemble atherosclerotic foam cells and signature gene expression reveals partial TREM2 dependence (A) UMAP plot displaying clustering of TREM2WT/WTxMGs isolated from 7-month-old 5X-hCSF1 mice (n=3 mice; 22,107 cells; WT xMGs per mouse (5987, 7876, 8244) and R47H xMGs per mouse (3939, 5571); B UMAP plot displaying clustering of TREM2R47H/R47HxMGs isolated from 7-month-old 5X-hCSF1 mice (n=2 mice; 9,510 cells); C A dot plot reveals top marker genes that are significantly up- or downregulated for each of the seven clusters (FDR-adjusted p-value < 0.01); (D) Barplot displaying the average percentage of cells making up the 7 unique xMG clusters; E Volcano plot displaying genes significantly up- and downregulated when comparing all TREM2R47H/R47H cells vs. all TREM2WT/WT cells; F-G UMAP plots displaying the module scores for 7 key DAM signature genes and 29 Foam cell signature genes identified in (Fernandezet al., [41]) (Additional File 1) in TREM2WT/WT (F) and TREM2R47H/R47H(G); H A dot plot reveals foam cell genes are particularly enriched in the DAM cell cluster (FDR-adjusted p-value < 0.01). Size of the circles indicate the percentage of cells expressing that gene and color indicates average expression levels; I Violin plots demonstrate foam cell signature genes are particularly enriched in the DAM cell cluster vs. other clusters, and are significantly (adjusted p-value < 0.01; LFC≥0.01) albeit subtly downregulated in R47H cells when comparing all TREM2R47H/R47H (blue) vs. all TREM2WT/WT cells (green) via pseudobulk analysis (Additional File 1)](/paper-figures/b9f4e2567f974f91b0c8e544c85b4ca1/plaque-associated-human-microglia-accumulate-lipid-droplets-in-a-chimeric-model-figure-1.jpg)
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“Mutations affecting the TREM2 function impair microglial activation (37) and reduce their ability to accumulate LDs in the AD brain (38).”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [38]
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“LDAM were also observed in chimaeric human–mouse AD models6.”
From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [6]
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“human iPSC-derived microglia were enriched in LDs in a chimeric mouse model of AD37”
From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [37]
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Metadata
- Authors
- Claes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., Lim, T. E., Hidalgo, J. L. S., Spitale, R. C., Davtyan, H., & Blurton-Jones, M.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Claes, Christel
- Blurton-Jones, Mathew
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2021-07-23
- Volume
- 16
- Issue
- 1
- Pages
- 50-50
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC8305935
- OpenAlex
- W3184188306
- Cited by
- 197
- References
- 53
- Citations by year
- 2026: 38 · 2025: 44 · 2024: 44 · 2023: 31 · 2022: 38 · 2021: 1
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- BrightFocus Foundation (A2020451F)
- National Institutes of Health (AG048099, AG056303, AG061895)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- Alzheimer's disease, disease-associated microglia, lipid droplets, TREM2, amyloid plaques, chimeric mouse model, CD9, apoE secretion, microglial activation, foam cells
- MeSH terms
- Alzheimer Disease, Animals, Brain, Chimera, Disease Models, Animal, Humans, Membrane Glycoproteins, Receptors, Immunologic, Microglia, Mice, Heterografts, Lipid Droplets
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