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PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology
Evan J Messenger, Sydney A Baar, Logan M Bedford, Andy P Tsai, Peter Bor-Chian Lin, Chloe A Ferguson, Guixiang Xu, Abigail Wallace et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025-05
Topic: Inflammation, microglia and astrocytes
In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques. Transcriptomic analysis revealed perturbations in immune-related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences. Human transcriptomics revealed positive correlations between PLCG2 and TREM2 independent of pathological scores. PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation. These findings clarify the mechanisms of risk and protective PLCG2 variants. HIGHLIGHTS: The role of phospholipase C gamma 2 (PLCG2) deficiency in response to amyloid beta (Aβ) pathology was investigated in 5xFAD mice and with human cortical transcriptomics. PLCG2 deficiency significantly reduces triggering receptor expressed on myeloid cells 2 (TREM2) expression, while TREM2 deficiency increases PLCG2 expression. PLCG2 expression predicts TREM2 expression in human cortex independent of pathology. PLCG2 and TREM2 deficiencies similarly impair microglial responses to Aβ plaques, exacerbate neuronal pathology, and impair gene expression associated with immune responses. PLCG2 deficiency confers distinct transcriptional perturbations from TREM2 deficiency. PLCG2 may play an upstream role in the regulation of the TREM2-mediated immune response.
Key findings
- In 5xFAD mice, the absence of PLCG2 resulted in reduced TREM2 expression and impaired microglial associations with amyloid beta plaques.
- Transcriptomic analysis revealed perturbations in immune-related pathways shared between PLCG2 and TREM2 deficiencies, as well as distinct differences.
- Human transcriptomics revealed positive correlations between PLCG2 and TREM2 independent of pathological scores.
- PLCG2 is a critical component of TREM2 signal transduction and may play an upstream role in TREM2 regulation.
- These findings clarify the mechanisms of risk and protective PLCG2 variants.
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Study details
- Evidence strengthLow
How this study scored 46/100
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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 2025 — 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40346446) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Messenger, E. J., Baar, S. A., Bedford, L. M., Tsai, A. P., Lin, P. B.-C., Ferguson, C. A., et al. (2025). PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.70231
Vancouver
Messenger EJ, Baar SA, Bedford LM, Tsai AP, Lin PB.-C, Ferguson CA, et al. PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2025. doi:10.1002/alz.70231. PMID: 40346446.
BibTeX
@article{messenger2025-40346446,
author = {Messenger, Evan J and Baar, Sydney A and Bedford, Logan M and Tsai, Andy P and Lin, Peter Bor-Chian and Ferguson, Chloe A and Xu, Guixiang and Wallace, Abigail and others},
title = {{PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2025},
doi = {10.1002/alz.70231},
pmid = {40346446},
url = {https://doi.org/10.1002/alz.70231}
}
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