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AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
Sayed FA, Kodama L, Fan L, Carling GK, Udeochu JC, Le D, Li Q, Zhou L et al.. Science translational medicine, 2021-12-01
Topic: Brain proteins, microglia and lab models
Plain-language summary
The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 ( TREM2 ), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)– TREM2 , we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice.
What this study adds
Evidence grade: Low
In brain tissue from people with Alzheimer's and in mice, the R47H TREM2 variant was linked to more inflammatory microglia and, in female mice, worse tau-related memory problems. This is early research combining human tissue analysis and animal models, not a treatment.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Sayed, F. A., Kodama, L., Fan, L., Carling, G. K., Udeochu, J. C., Le, D., et al. (2021). AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Science translational medicine. https://doi.org/10.1126/scitranslmed.abe3947
Vancouver
Sayed FA, Kodama L, Fan L, Carling GK, Udeochu JC, Le D, et al. AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Science translational medicine. 2021. doi:10.1126/scitranslmed.abe3947. PMID: 34851693.
BibTeX
@article{sayed2021-34851693,
author = {Sayed, F. A. and Kodama, L. and Fan, L. and Carling, G. K. and Udeochu, J. C. and Le, D. and Li, Q. and Zhou, L. and others},
title = {{AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation}},
journal = {Science translational medicine},
year = {2021},
doi = {10.1126/scitranslmed.abe3947},
pmid = {34851693},
url = {https://doi.org/10.1126/scitranslmed.abe3947}
}
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.
Key findings
- Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)– TREM2 , we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2.
- We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice.
- Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures.
- Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils.
Why it matters
In brain tissue from people with Alzheimer's and in mice, the R47H TREM2 variant was linked to more inflammatory microglia and, in female mice, worse tau-related memory problems. This is early research combining human tissue analysis and animal models, not a treatment.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 53/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science translational medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 158 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 22.6 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 3 / 6 | Cited 8.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 15 other studies in this library |
| Still being cited | 3 / 4 | Cited 91 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Li Gan: h-index 71 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Massachusetts Institute of Technology: institution h-index 2,557 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 17 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34851693) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1126/scitranslmed.abe3947
- PubMed: 34851693
- Original source →
- Free full text: eScholarship (California Digital Library) →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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