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TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge
Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, Llapashtica C, Wang J et al.. Neuron, 2020-01-02
Topic: Brain proteins, microglia and lab models
Loss-of-function (LOF) variants of TREM2, an immune receptor expressed in microglia, increase Alzheimer's disease risk. TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown. Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage.
Key findings
- TREM2 senses lipids and mediates myelin phagocytosis, but its role in microglial lipid metabolism is unknown.
- Combining chronic demyelination paradigms and cell sorting with RNA sequencing and lipidomics, we find that wild-type microglia acquire a disease-associated transcriptional state, while TREM2-deficient microglia remain largely homeostatic, leading to neuronal damage.
- TREM2-deficient microglia phagocytose myelin debris but fail to clear myelin cholesterol, resulting in cholesteryl ester (CE) accumulation.
- CE increase is also observed in APOE-deficient glial cells, reflecting impaired brain cholesterol transport.
Why it matters
Variants that weaken TREM2, an immune receptor on the brain's microglia, are linked to higher Alzheimer's risk, and this laboratory study asked how TREM2 affects the way these cells handle fats. In long-running myelin-damage experiments, microglia lacking TREM2 still ate myelin debris but could not clear its cholesterol, which built up as cholesteryl ester; they also stayed in a resting ("largely homeostatic") state instead of switching to a disease-response state, which the authors link to nerve-cell damage. A similar cholesteryl-ester build-up was seen in glial cells lacking APOE; this is cell-biology research, not a test of any Alzheimer's treatment.
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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 (Neuron) |
| Journal's citation record | 4 / 4 | Neuron: journal h-index 689 (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 | 2020 — 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 | 6 / 7 | Cited 747 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 93.4 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 5 / 6 | Cited 31.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 63 other studies in this library |
| Still being cited | 4 / 4 | Cited 369 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Gilbert Di Paolo: h-index 76 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Denali Therapeutics (United States): institution h-index 217 (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 31902528) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 53 / 100 | — |
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APA 7th
Nugent, A. A., Lin, K., van Lengerich, B., Lianoglou, S., Przybyla, L., Davis, S. S., et al. (2020). TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Neuron. https://doi.org/10.1016/j.neuron.2019.12.007
Vancouver
Nugent AA, Lin K, van Lengerich B, Lianoglou S, Przybyla L, Davis SS, et al. TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge. Neuron. 2020. doi:10.1016/j.neuron.2019.12.007. PMID: 31902528.
BibTeX
@article{nugent2020-31902528,
author = {Nugent, A. A. and Lin, K. and van Lengerich, B. and Lianoglou, S. and Przybyla, L. and Davis, S. S. and Llapashtica, C. and Wang, J. and others},
title = {{TREM2 Regulates Microglial Cholesterol Metabolism upon Chronic Phagocytic Challenge}},
journal = {Neuron},
year = {2020},
doi = {10.1016/j.neuron.2019.12.007},
pmid = {31902528},
url = {https://doi.org/10.1016/j.neuron.2019.12.007}
}
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