{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:25:00Z","timestamp":1792531500749,"version":"4.5.0"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000026","name":"Canadian Government | CIHR | Institute of Aging","doi-asserted-by":"publisher","award":["185865"],"award-info":[{"award-number":["185865"]}],"id":[{"id":"10.13039\/501100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:p>Altered \u03b2-amyloid (A\u03b2) homeostasis is a critical event triggering the shift from healthy aging to Alzheimer disease (AD) through the overproduction and impaired clearance of A\u03b2 peptides. The A\u03b2-degrading enzymes (ADEs) are a collective group of proteases that normally promote clearance to counteract A\u03b2-induced neurodegeneration. We previously discovered that the beta-site amyloid precursor protein cleaving enzyme 1 is an atypical ADE that produces the nontoxic fragment A\u03b234 by recognizing 40- or 42-residue-long A\u03b2 peptides as substrates in vitro and in vivo. Here, we examined other known ADEs for their potential roles in degrading A\u03b234, A\u03b240, and A\u03b242. 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 A\u03b234 but not A\u03b240 or A\u03b242. Notably, we found that ECE1 cleaves A\u03b234, an indicator of amyloid clearance, to a unique and unusually stable A\u03b220-34 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 A\u03b234) compared to other cell types. Given A\u03b234 is an indicator for prodromal AD, we postulate that our collective findings (i.e., generation of A\u03b234 and A\u03b220-34 intermediates within the \u201camyloidolytic\u201d degradation pathway) will generate a set of biomarkers to detect amyloid clearance activity in vivo.<\/jats:p>","DOI":"10.1073\/pnas.2507450122","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T19:06:01Z","timestamp":1761591961000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme A\u03b2 degradation pathway"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9381-4120","authenticated-orcid":false,"given":"Irem","family":"Ulku","sequence":"first","affiliation":[{"name":"Integrated Program in Neuroscience, McGill University","place":["Montreal, Canada"]},{"name":"Department of Pharmacology and Therapeutics, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima El","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7427-7449","authenticated-orcid":false,"given":"Mark A.","family":"Hancock","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4871-2635","authenticated-orcid":false,"given":"Hedi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Integrated Program in Neuroscience, McGill University","place":["Montreal, Canada"]},{"name":"Department of Pharmacology and Therapeutics, McGill University","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9664-3518","authenticated-orcid":false,"given":"Gael","family":"Cagnone","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]},{"name":"Department of Ophthalmology, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]},{"name":"Department of Pharmacology, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3877-9614","authenticated-orcid":false,"given":"Jean-Sebastien","family":"Joyal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]},{"name":"Department of Ophthalmology, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]},{"name":"Department of Pharmacology, Centre Hospitalier Universitaire Sainte Justine Research Center","place":["Montreal, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4948-0741","authenticated-orcid":false,"given":"Teddy A. 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