{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T22:43:13Z","timestamp":1786574593642,"version":"build-2736575974"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Higher Education of the Russian Federation allocated to the Center for Precision Genome Editing and Genetic Technologies for Biomedicine.","award":["grant \u2116075-15-2019-1789"],"award-info":[{"award-number":["grant \u2116075-15-2019-1789"]}]},{"DOI":"10.13039\/501100016971","name":"Lomonosov Moscow State University","doi-asserted-by":"publisher","award":["121041500039-8"],"award-info":[{"award-number":["121041500039-8"]}],"id":[{"id":"10.13039\/501100016971","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100016971","name":"Lomonosov Moscow State University","doi-asserted-by":"publisher","award":["121041500039-8"],"award-info":[{"award-number":["121041500039-8"]}],"id":[{"id":"10.13039\/501100016971","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Analysis of existing mutations of Angiotensin-I-Converting Enzyme (ACE) led us to hypothesize that the carriers of damaging ACE mutations (accompanied by low ACE levels) could be at risk for the development of late-onset Alzheimer\u2019s disease (AD).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/Principal findings<\/jats:title>\n<jats:p>We quantified blood ACE levels in EDTA-containing plasma from 15 patients with 11 different heterozygous ACE mutations and estimated the effects of these mutations on ACE phenotypes, using a set of mAbs to ACE and two ACE substrates. We confirmed prior observations that the relatively frequent Y215C mutation in the N domain of ACE (present in ~1% of the population) is associated with both Alzheimer\u2019s disease (AD) and reduced plasma levels of ACE (~50% of controls), indicating that it likely results in a transport-deficient protein. In addition, we identified another 4 mutations in both ACE domains (M118T, C734Y, V992M and V997M) which are also associated with decreased ACE levels in the blood, and, thus, could be putative risk factors for late-onset AD. One of these mutations, C734Y, is likely transport-deficient, while the other mutations appear to influence ACE catalytic properties. The precipitation of mutant M118T by mAb 2D1 and ACE mutant C734Y by mAb 3F10 increased 2-3-fold compared to native ACE, and therefore, these mAbs could be markers of these mutations. Also, we identified a mutation I989T, which is associated with increased ACE levels in the blood.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/Significance<\/jats:title>\n<jats:p>Conducting a systematic analysis of blood ACE levels in patients with ACE mutations holds promise for identifying individuals with low blood ACE levels. Such individuals may be at increased risk for late-onset AD. The patients with transport-deficient ACE mutations may benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously using a cell model of the transport-deficient ACE mutation, Q1069R [Danilov et al, PLoS One, 2010].<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0308289","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T17:28:32Z","timestamp":1728408512000},"page":"e0308289","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Effect of ACE mutations on blood ACE phenotype parameters"],"prefix":"10.1371","volume":"19","author":[{"given":"Olga V.","family":"Kryukova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1343-2550","authenticated-orcid":true,"given":"Dmitry O.","family":"Korostin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5930-1965","authenticated-orcid":true,"given":"Vera A.","family":"Belova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5294-3033","authenticated-orcid":true,"given":"Valery V.","family":"Cheranev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4228-6114","authenticated-orcid":true,"given":"Zhanna A.","family":"Repinskaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-2851","authenticated-orcid":true,"given":"Igor V.","family":"Uporov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven M.","family":"Dudek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Kost","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis V.","family":"Rebrikov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-4545","authenticated-orcid":true,"given":"Sergei M.","family":"Danilov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"pone.0308289.ref001","doi-asserted-by":"crossref","first-page":"162","DOI":"10.3390\/biomedicines12010162","article-title":"Carriers of heterozygous loss-of-function ACE mutations are at risk for Alzheimer\u2019s disease","volume":"12","author":"SM Danilov","year":"2024","journal-title":"Biomedicines"},{"key":"pone.0308289.ref002","author":"OV Kryukova","year":"2024"},{"key":"pone.0308289.ref003","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/S0140-6736(05)63300-4","article-title":"Presenilin polymorphisms in Alzheimer\u2019s disease","volume":"350","author":"GI Korovaitseva","year":"1997","journal-title":"Lancet"},{"key":"pone.0308289.ref004","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/s41588-020-00776-w","article-title":"Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer\u2019s disease risk genes","volume":"53","author":"J Schwartzentruber","year":"2021","journal-title":"Nat Genet"},{"key":"pone.0308289.ref005","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/5009","article-title":"Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer\u2019s disease","volume":"21","author":"PG Kehoe","year":"1999","journal-title":"Nat Genet"},{"key":"pone.0308289.ref006","doi-asserted-by":"crossref","first-page":"e0150079","DOI":"10.1371\/journal.pone.0150079","article-title":"Influence of coding variability in APP-A\u03b2 metabolism genes in sporadic Alzheimer\u2019s disease","volume":"11","author":"C Sassi","year":"2016","journal-title":"PLOS One"},{"key":"pone.0308289.ref007","doi-asserted-by":"crossref","first-page":"47863","DOI":"10.1074\/jbc.M104068200","article-title":"Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta); 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