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Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme Aβ degradation pathway
Irem Ulku, Fatima El Ansari, Mark A. Hancock, Hedi Zhou, Gaël Cagnone, Jean‐Sébastien Joyal, Teddy A. J. Fisher, Timothy E. Kennedy et al.. Proceedings of the National Academy of Sciences, 2025-10-27
Topic: Brain proteins, microglia and lab models
Altered β-amyloid (Aβ) homeostasis is a critical event triggering the shift from healthy aging to Alzheimer disease (AD) through the overproduction and impaired clearance of Aβ peptides. The Aβ-degrading enzymes (ADEs) are a collective group of proteases that normally promote clearance to counteract Aβ-induced neurodegeneration. We previously discovered that the beta-site amyloid precursor protein cleaving enzyme 1 is an atypical ADE that produces the nontoxic fragment Aβ34 by recognizing 40- or 42-residue-long Aβ peptides as substrates in vitro and in vivo. Here, we examined other known ADEs for their potential roles in degrading Aβ34, Aβ40, and Aβ42. By genetic, cellular, and pharmacological approaches, we identified and characterized endothelin-converting enzyme 1 (ECE1) in a human neuroblastoma cell line, human brain vascular pericytes, and primary rat cortical cultures as a major enzyme degrading Aβ34 but not Aβ40 or Aβ42. Notably, we found that ECE1 cleaves Aβ34, an indicator of amyloid clearance, to a unique and unusually stable Aβ20-34 fragment that has the potential to serve as a measurable biomarker. Biocomputational analyses from non-AD controls and individuals with AD pathology showed that the highest messenger ribonucleic acid (mRNA) levels of ECE1 expression were found in pericytes (i.e., cells within the brain microvasculature that are known to produce Aβ34) compared to other cell types. Given Aβ34 is an indicator for prodromal AD, we postulate that our collective findings (i.e., generation of Aβ34 and Aβ20-34 intermediates within the "amyloidolytic" degradation pathway) will generate a set of biomarkers to detect amyloid clearance activity in vivo.
Key findings
- Notably, we found that ECE1 cleaves Aβ34, an indicator of amyloid clearance, to a unique and unusually stable Aβ20-34 fragment that has the potential to serve as a measurable biomarker.
- Biocomputational analyses from non-AD controls and individuals with AD pathology showed that the highest messenger ribonucleic acid (mRNA) levels of ECE1 expression were found in pericytes (i.e., cells within the brain microvasculature that are known to produce Aβ34) compared to other cell types.
Why it matters
This laboratory work identifies endothelin-converting enzyme 1 as an enzyme that degrades Aβ34 in cells and proposes a fragment as a possible measurable biomarker. It does not test any treatment in people and does not show an effect on preventing or curing Alzheimer's disease.
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Study details
- Evidence strengthLow
How this study scored 36/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (OpenAlex, 2026-10-29) |
| 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 | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 0 / 6 | Cited 0.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Gerd Multhaup: h-index 86 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | McGill University: institution h-index 1,373 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41144673) |
| Free to read | 2 / 2 | Free to read |
| Total | 36 / 100 | — |
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Read the original
- DOI: 10.1073/pnas.2507450122
- PubMed: 41144673
- Original source →
- Free full text: Proceedings of the National Academy of Sciences →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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
Ulku, I., El Ansari, F., Hancock, M. A., Zhou, H., Cagnone, G., Joyal, J., et al. (2025). Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme Aβ degradation pathway. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2507450122
Vancouver
Ulku I, El Ansari F, Hancock MA, Zhou H, Cagnone G, Joyal J, et al. Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme Aβ degradation pathway. Proceedings of the National Academy of Sciences. 2025. doi:10.1073/pnas.2507450122. PMID: 41144673.
BibTeX
@article{ulku2025-41144673,
author = {Ulku, Irem and El Ansari, Fatima and Hancock, Mark A. and Zhou, Hedi and Cagnone, Gaël and Joyal, Jean‐Sébastien and Fisher, Teddy A. J. and Kennedy, Timothy E. and others},
title = {{Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme Aβ degradation pathway}},
journal = {Proceedings of the National Academy of Sciences},
year = {2025},
doi = {10.1073/pnas.2507450122},
pmid = {41144673},
url = {https://doi.org/10.1073/pnas.2507450122}
}
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