The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation
Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N et al.. Nature neuroscience, 2023-11-13
Topic: Brain proteins, microglia and lab models
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
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APA 7th
Nelson, M. R., Liu, P., Agrawal, A., Yip, O., Blumenfeld, J., Traglia, M., et al. (2023). The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nature neuroscience. https://doi.org/10.1038/s41593-023-01480-8
Vancouver
Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, et al. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nature neuroscience. 2023. doi:10.1038/s41593-023-01480-8. PMID: 37957317.
BibTeX
@article{nelson2023-37957317,
author = {Nelson, M. R. and Liu, P. and Agrawal, A. and Yip, O. and Blumenfeld, J. and Traglia, M. and Kim, M. J. and Koutsodendris, N. and others},
title = {{The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation}},
journal = {Nature neuroscience},
year = {2023},
doi = {10.1038/s41593-023-01480-8},
pmid = {37957317},
url = {https://doi.org/10.1038/s41593-023-01480-8}
}
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Key findings
- We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.
- Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner.
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Study details
- Evidence strengthLow
How this study scored 47/100
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 and multi-centre collaboration, so those were left out: it earned 27 of the 58 points we could judge it on, which is 47 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature neuroscience) |
| 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 37957317) |
| Free to read | 2 / 2 | Free to read |
| Points | 27 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 27 of the 58 points we could judge it on is 47 out of 100. |
| Total | 47 / 100 | — |
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