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The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism
Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, Focke C, Deußing M et al.. The EMBO journal, 2017-05-30
Topic: Brain proteins, microglia and lab models
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation.
Key findings
- Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown.
- Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation.
- Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p.T66M mutation.
- Trem2 p.T66M knock-in mice show delayed resolution of inflammation upon in vivo lipopolysaccharide stimulation and cultured macrophages display significantly reduced phagocytic activity.
Why it matters
People who inherit two copies of the TREM2 p.T66M mutation develop an FTD-like syndrome, and this study built a gene-edited mouse carrying it to learn how. In the mice, the mutant Trem2 protein built up inside cells in an immature form and less soluble Trem2 was made, "similar to patients with the homozygous p.T66M mutation"; the mice were slower to resolve an inflammation triggered with a bacterial toxin, and their cultured macrophages were less able to engulf material — findings the authors describe as consistent with loss of function. This is mouse and cell work on a frontotemporal-dementia mutation; it does not test a treatment and does not show how TREM2 affects Alzheimer's disease in people.
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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 randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The EMBO journal) |
| Journal's citation record | 4 / 4 | The EMBO Journal: journal h-index 563 (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 | 2 / 5 | 2017 — within 10 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 254 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 23.1 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 4 / 6 | Cited 11.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 47 other studies in this library |
| Still being cited | 3 / 4 | Cited 62 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Christian Haass: h-index 139 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Ludwig-Maximilians-Universität München: institution h-index 1,224 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28559417) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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Read the original
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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
Kleinberger, G., Brendel, M., Mracsko, E., Wefers, B., Groeneweg, L., Xiang, X., et al. (2017). The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. The EMBO journal. https://doi.org/10.15252/embj.201796516
Vancouver
Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. The EMBO journal. 2017. doi:10.15252/embj.201796516. PMID: 28559417.
BibTeX
@article{kleinberger2017-28559417,
author = {Kleinberger, G. and Brendel, M. and Mracsko, E. and Wefers, B. and Groeneweg, L. and Xiang, X. and Focke, C. and Deußing, M. and others},
title = {{The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism}},
journal = {The EMBO journal},
year = {2017},
doi = {10.15252/embj.201796516},
pmid = {28559417},
url = {https://doi.org/10.15252/embj.201796516}
}
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