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Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity
Katerina Konstantoulea, Meine Ramakers, Sarah C Borrie, Dries T'Syen, Daan Moechars, Malgorzata A Sliwinska, Brajabandhu Pradhan, Giulia Albertini et al.. Proceedings of the National Academy of Sciences of the United States of America, 2026-03-02
Topic: Inflammation, microglia and astrocytes
The prevailing view frames microglia and macrophages as guardians against amyloid beta (Aβ) accumulation in Alzheimer's disease (AD). Here, we overturn this paradigm by demonstrating that human phagocytic cells, including differentiated THP-1 macrophages and hESC-derived microglia, are not merely passive responders but active producers of extracellular, seeding-competent Aβ42 fibrils, the amyloid species most strongly linked to parenchymal plaque formation and neurodegeneration. These cell-generated aggregates differ structurally and functionally from synthetic fibrils, displaying enhanced seeding and tau cross-seeding activity in biosensor models. Notably, Aβ42 fibril formation in this system requires active cellular processes and is exacerbated by loss of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a major AD risk gene. Transcriptomic profiling reveals an early inflammatory response resembling microglial states observed in human AD models. Together, these findings support emerging evidence from in vivo studies that macrophages and microglia can influence amyloid seeding and introduce a human-relevant in vitro platform to explore how Aβ aggregation intersects with innate immune function and genetic risk. Our results reinforce the concept that microglia may play a dual role in AD, acting both as responders and inadvertent facilitators of amyloid assembly, with implications for early therapeutic intervention.
Key findings
- Together, these findings support emerging evidence from in vivo studies that macrophages and microglia can influence amyloid seeding and introduce a human-relevant in vitro platform to explore how Aβ aggregation intersects with innate immune function and genetic risk.
- Our results reinforce the concept that microglia may play a dual role in AD, acting both as responders and inadvertent facilitators of amyloid assembly, with implications for early therapeutic intervention.
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Study details
- Evidence strengthLow
How this study scored 45/100
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 25 of the 56 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America) |
| 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 | 5 / 5 | 2026 — within 1 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 41770935) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 25 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 25 of the 56 points we could judge it on is 45 out of 100. |
| Total | 45 / 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
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Konstantoulea, K., Ramakers, M., Borrie, S. C., T'Syen, D., Moechars, D., Sliwinska, M. A., et al. (2026). Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2516774123
Vancouver
Konstantoulea K, Ramakers M, Borrie SC, T'Syen D, Moechars D, Sliwinska MA, et al. Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity. Proceedings of the National Academy of Sciences of the United States of America. 2026. doi:10.1073/pnas.2516774123. PMID: 41770935.
BibTeX
@article{konstantoulea2026-41770935,
author = {Konstantoulea, Katerina and Ramakers, Meine and Borrie, Sarah C and T'Syen, Dries and Moechars, Daan and Sliwinska, Malgorzata A and Pradhan, Brajabandhu and Albertini, Giulia and others},
title = {{Phagocytes as plaque catalysts: Human macrophages generate seeding-competent Aβ42 fibrils with cross-seeding activity}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
doi = {10.1073/pnas.2516774123},
pmid = {41770935},
url = {https://doi.org/10.1073/pnas.2516774123}
}
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