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Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia
Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, Lin K, Shi J et al.. Nature neuroscience, 2020-06-08
Topic: Brain proteins, microglia and lab models
Human genetic data indicate that microglial dysfunction contributes to the pathology of Alzheimer's disease (AD), exemplified by the identification of coding variants in triggering receptor expressed on myeloid cells 2 (TREM2) and, more recently, in PLCG2, a phospholipase-encoding gene expressed in microglia. Although studies in mouse models have implicated specific Trem2-dependent microglial functions in AD, the underlying molecular mechanisms and translatability to human disease remain poorly defined. In this study, we used genetically engineered human induced pluripotent stem cell-derived microglia-like cells to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism.
Key findings
- Although studies in mouse models have implicated specific Trem2-dependent microglial functions in AD, the underlying molecular mechanisms and translatability to human disease remain poorly defined.
- In this study, we used genetically engineered human induced pluripotent stem cell-derived microglia-like cells to show that TREM2 signals through PLCγ2 to mediate cell survival, phagocytosis, processing of neuronal debris, and lipid metabolism.
- Loss of TREM2 or PLCγ2 signaling leads to a shared signature of transcriptional dysregulation that underlies these phenotypes.
- Independent of TREM2, PLCγ2 also signals downstream of Toll-like receptors to mediate inflammatory responses.
Why it matters
Both TREM2 and PLCG2 carry gene variants linked to Alzheimer's disease, and both are active in microglia, the brain's immune cells. Working with lab-grown human microglia-like cells, this study found that TREM2 signals through PLCγ2 to support cell survival, clearing and processing of neuronal debris, and lipid metabolism, and that PLCγ2 separately drives inflammatory responses through Toll-like receptors. This is lab work on cells, not people. It points to PLCγ2 as a shared control point but does not show a treatment for Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 49/100
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 | 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 | 5 / 7 | Cited 233 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 29.1 citations a year over 8 year(s) since 2020 |
| Impact for its field and year | 4 / 6 | Cited 11.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 21 other studies in this library |
| Still being cited | 3 / 4 | Cited 98 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Joseph W. Lewcock: h-index 39 (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 32514138) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 49 / 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
Andreone, B. J., Przybyla, L., Llapashtica, C., Rana, A., Davis, S. S., van Lengerich, B., et al. (2020). Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nature neuroscience. https://doi.org/10.1038/s41593-020-0650-6
Vancouver
Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, et al. Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nature neuroscience. 2020. doi:10.1038/s41593-020-0650-6. PMID: 32514138.
BibTeX
@article{andreone2020-32514138,
author = {Andreone, B. J. and Przybyla, L. and Llapashtica, C. and Rana, A. and Davis, S. S. and van Lengerich, B. and Lin, K. and Shi, J. and others},
title = {{Alzheimer's-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia}},
journal = {Nature neuroscience},
year = {2020},
doi = {10.1038/s41593-020-0650-6},
pmid = {32514138},
url = {https://doi.org/10.1038/s41593-020-0650-6}
}
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