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Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology
Wenhui Qiao, Yixing Chen, Jun Zhong, Benjamin J Madden, Cristine M Charlesworth, Yuka A Martens, Chia-Chen Liu, Joshua Knight et al.. Molecular neurodegeneration, 2023-01-31
Topic: Inflammation, microglia and astrocytes
Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Qiao, W., Chen, Y., Zhong, J., Madden, B. J., Charlesworth, C. M., Martens, Y. A., et al. (2023). Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology. Molecular neurodegeneration. https://doi.org/10.1186/s13024-023-00599-3
Vancouver
Qiao W, Chen Y, Zhong J, Madden BJ, Charlesworth CM, Martens YA, et al. Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology. Molecular neurodegeneration. 2023. doi:10.1186/s13024-023-00599-3. PMID: 36721205.
BibTeX
@article{qiao2023-36721205,
author = {Qiao, Wenhui and Chen, Yixing and Zhong, Jun and Madden, Benjamin J and Charlesworth, Cristine M and Martens, Yuka A and Liu, Chia-Chen and Knight, Joshua and others},
title = {{Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology}},
journal = {Molecular neurodegeneration},
year = {2023},
doi = {10.1186/s13024-023-00599-3},
pmid = {36721205},
url = {https://doi.org/10.1186/s13024-023-00599-3}
}
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Key findings
- Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum.
- Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling.
- In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-β (Aβ) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines.
- Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aβ.
- TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice.
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Study details
- Evidence strengthLow
How this study scored 41/100
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, multi-centre collaboration and free to read, so those were left out: it earned 23 of the 56 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| 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 36721205) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 23 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 23 of the 56 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
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