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Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology
Mancuso R, Fattorelli N, Martinez-Muriana A, Davis E, Wolfs L, Van Den Daele J, Geric I, Premereur J et al.. Nature neuroscience, 2024-03-27
Topic: Brain proteins, microglia and lab models
Microglia are central players in Alzheimer's disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the App NL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques.
Key findings
- To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the App NL-G-F model of amyloid pathology and wild-type controls.
- Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques.
- The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers.
- Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2 R47H expression in the transplanted microglia modulate these responses differentially.
Why it matters
Human stem cell-derived microglia grown inside the brains of amyloid-model mice (138,577 single cells profiled) took on a disease-associated profile like mouse microglia, but with a stronger HLA state the authors call "likely related to antigen presentation in response to amyloid plaques", plus a pro-inflammatory cytokine/chemokine response to Aβ oligomers. Deleting TREM2 or APOE, or using APOE variants or TREM2 R47H in the transplanted cells, changed these responses in different ways. This is a cell-in-mouse study with no patients and no treatment tested, so it describes how human immune cells react, not a way to prevent or treat Alzheimer's.
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Study details
- Evidence strengthLow
How this study scored 59/100
Published in a leading specialty 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 | 9 / 10 | Tier 2 — leading specialty journal (Nature neuroscience) |
| Journal's citation record | 4 / 4 | Nature Neuroscience: journal h-index 593 (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 | 4 / 5 | 2024 — within 3 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 161 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 40.2 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 5 / 6 | Cited 21.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 9 other studies in this library |
| Still being cited | 3 / 4 | Cited 155 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Bart De Strooper: h-index 146 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38539015) |
| Free to read | 2 / 2 | Free to read |
| Total | 59 / 100 | — |
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Read the original
- DOI: 10.1038/s41593-024-01600-y
- PubMed: 38539015
- Original source →
- Free full text: Nature Neuroscience →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Mancuso, R., Fattorelli, N., Martinez-Muriana, A., Davis, E., Wolfs, L., Van Den Daele, J., et al. (2024). Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology. Nature neuroscience. https://doi.org/10.1038/s41593-024-01600-y
Vancouver
Mancuso R, Fattorelli N, Martinez-Muriana A, Davis E, Wolfs L, Van Den Daele J, et al. Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology. Nature neuroscience. 2024. doi:10.1038/s41593-024-01600-y. PMID: 38539015.
BibTeX
@article{mancuso2024-38539015,
author = {Mancuso, R. and Fattorelli, N. and Martinez-Muriana, A. and Davis, E. and Wolfs, L. and Van Den Daele, J. and Geric, I. and Premereur, J. and others},
title = {{Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-β pathology}},
journal = {Nature neuroscience},
year = {2024},
doi = {10.1038/s41593-024-01600-y},
pmid = {38539015},
url = {https://doi.org/10.1038/s41593-024-01600-y}
}
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