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PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease
Huong T Phuong, Rodrigo F Tomas, Cemal Akmese, Ana Mijares, Isabella M Gerstin, Shu Guo, Logan R Bell, Ross Ellwood et al.. Acta neuropathologica, 2025-11-08
Topic: Disease mechanisms in lab and animal studies
Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.
Key findings
- Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases.
- A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases.
- Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining.
- In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.
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 (Acta neuropathologica) |
| 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 41204969) |
| 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 | — |
What each of these 20 components measures, and what this score is not →
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
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APA 7th
Phuong, H. T., Tomas, R. F., Akmese, C., Mijares, A., Gerstin, I. M., Guo, S., et al. (2025). PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02954-8
Vancouver
Phuong HT, Tomas RF, Akmese C, Mijares A, Gerstin IM, Guo S, et al. PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02954-8. PMID: 41204969.
BibTeX
@article{phuong2025-41204969,
author = {Phuong, Huong T and Tomas, Rodrigo F and Akmese, Cemal and Mijares, Ana and Gerstin, Isabella M and Guo, Shu and Bell, Logan R and Ellwood, Ross and others},
title = {{PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02954-8},
pmid = {41204969},
url = {https://doi.org/10.1007/s00401-025-02954-8}
}
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