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TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation
Moutinho M, Coronel I, Tsai AP, Di Prisco GV, Pennington T, Atwood BK, Puntambekar SS, Smith DC et al.. Genome medicine, 2023-02-20
Topic: Brain proteins, microglia and lab models
Background TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer's disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. Methods The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer's Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. Results Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230 ), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222 ) and ENST00000338469 (TREM2 219 ), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin. Conclusions TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.
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APA 7th
Moutinho, M., Coronel, I., Tsai, A. P., Di Prisco, G. V., Pennington, T., Atwood, B. K., et al. (2023). TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome medicine. https://doi.org/10.1186/s13073-023-01160-z
Vancouver
Moutinho M, Coronel I, Tsai AP, Di Prisco GV, Pennington T, Atwood BK, et al. TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome medicine. 2023. doi:10.1186/s13073-023-01160-z. PMID: 36805764.
BibTeX
@article{moutinho2023-36805764,
author = {Moutinho, M. and Coronel, I. and Tsai, A. P. and Di Prisco, G. V. and Pennington, T. and Atwood, B. K. and Puntambekar, S. S. and Smith, D. C. and others},
title = {{TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation}},
journal = {Genome medicine},
year = {2023},
doi = {10.1186/s13073-023-01160-z},
pmid = {36805764},
url = {https://doi.org/10.1186/s13073-023-01160-z}
}
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Key findings
- Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor.
- Results Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230 ), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222 ) and ENST00000338469 (TREM2 219 ), are moderately increased in specific brain regions of patients with AD.
- These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease.
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Study details
- Evidence strengthLow
How this study scored 43/100
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. 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 and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Genome medicine) |
| 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 | 3 / 5 | 2023 — 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) |
| 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 36805764) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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