Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease
Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, Lim TE, Hidalgo JLS et al.. Molecular neurodegeneration, 2021-07-23
Topic: Brain proteins, microglia and lab models
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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APA 7th
Claes, C., Danhash, E. P., Hasselmann, J., Chadarevian, J. P., Shabestari, S. K., England, W. E., et al. (2021). Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Molecular neurodegeneration. https://doi.org/10.1186/s13024-021-00473-0
Vancouver
Claes C, Danhash EP, Hasselmann J, Chadarevian JP, Shabestari SK, England WE, et al. Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease. Molecular neurodegeneration. 2021. doi:10.1186/s13024-021-00473-0. PMID: 34301296.
BibTeX
@article{claes2021-34301296,
author = {Claes, C. and Danhash, E. P. and Hasselmann, J. and Chadarevian, J. P. and Shabestari, S. K. and England, W. E. and Lim, T. E. and Hidalgo, J. L. S. and others},
title = {{Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease}},
journal = {Molecular neurodegeneration},
year = {2021},
doi = {10.1186/s13024-021-00473-0},
pmid = {34301296},
url = {https://doi.org/10.1186/s13024-021-00473-0}
}
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Key findings
- 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.
- 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.
- 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.
Why it matters
Human immune cells (microglia) transplanted into Alzheimer's model mice built up fat droplets around amyloid plaques, and their gene activity resembled the fat-laden "foam cells" of clogged arteries. Cells carrying the TREM2-R47H Alzheimer's risk variant stayed further from plaques, reacted less, and built up less fat, which the authors read as the fat build-up following from the cells' response to plaques. This was done in mice, at one age, and does not test any treatment for people.
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Study details
- Evidence strengthLow
How this study scored 50/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | 2 / 4 | Molecular Neurodegeneration: journal h-index 164 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 195 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 27.9 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 4 / 6 | Cited 9.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 10 other studies in this library |
| Still being cited | 3 / 4 | Cited 124 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Mathew M. Blurton-Jones: h-index 57 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of California, Irvine: institution h-index 1,195 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34301296) |
| Free to read | 2 / 2 | Free to read |
| Total | 50 / 100 | — |
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Read the original
- DOI: 10.1186/s13024-021-00473-0
- PubMed: 34301296
- Original source →
- Free full text: Molecular Neurodegeneration →
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